Chapter 193 :: Herpes Simplex
31
:: Adriana R. Marques & Jeffrey I. Cohen
HERPES SIMPLEX AT A GLANCE
Herpes simplex viruses (HSVs) are
common human DNA viral pathogens that
intermittently reactivate. After replication
in the skin or mucosa, the virus infects
the local nerve endings and ascends to
the ganglia where it becomes latent until
reactivation.
There are two types of HSV: HSV-1 and HSV-
2. HSV-1 is mostly associated with orofacial
disease, whereas HSV-2 usually causes
genital infection, but both can infect oral and
genital areas and cause acute and recurrent
infections.
Most of the adult population is seropositive
for HSV-1, and the majority of infections are
acquired in childhood. About one-fourth of
adults are infected with HSV-2 in the United
States. Acquisition of HSV-2 correlates with
sexual behavior.
Most primary HSV infections are
asymptomatic or not recognized, but
they can also cause severe disease.
Most recurrences are not symptomatic
(asymptomatic shedding), with most
transmissions occurring by asymptomatic
shedding.
Genital herpes is the most prevalent sexually
transmitted disease worldwide and is the
most common cause of ulcerative genital
disease, and it is an important risk factor
for acquisition and transmission of human
immunodeficiency virus.
HSV can cause diseases involving the
eye, central nervous system, and neonatal
infection. Cellular immunity defects are
a risk factor for severe and disseminated
disease.
Diagnosis is made by polymerase chain
reaction, viral culture, or serology,
depending on the clinical presentation.
Treatment is with acyclovir, valacyclovir,
or famciclovir. Regimens and dosages
vary with the clinical setting. Resistance is
rare in other than immunocompromised
patients.
EPIDEMIOLOGY
Herpes simplex virus (HSV) infections are common
worldwide and are caused by two closely related types
of HSV. Their main clinical manifestations are muco-
cutaneous infections, with HSV type 1 (HSV-1) being
mostly associated with orofacial disease, whereas HSV
type 2 (HSV-2) is usually associated with genital and
perigenital infection.
Chapter 193
The incidence of primary infection with HSV-1,
which is responsible for the vast majority of recur-
ring labial herpes, is greatest during childhood, when
30%60% of children are exposed to the virus. Rates
of infection with HSV-1 increase with age and reduced
socioeconomic status, the majority of persons age 30 or
::
older are seropositive for HSV-1.1,2 From 20% to 40%
Herpes Simplex
of the population have had episodes of herpes labia-
lis.3 The frequency of recurrent episodes is extremely
variable, and, in some studies, averages about once
per year,4 but there is evidence that the frequency and
severity of recurrent HSV-1 disease decrease over time.
Acquisition of HSV-2 correlates with sexual behav-
ior and the prevalence of the infection in the pool of
ones potential sexual partners. Antibodies to HSV-2
are rare in people before the onset of intimate sexual
activity and rise steadily thereafter. HSV-2 seropreva-
lence in the United States is 22% in persons 12 years of
age or older.5 The rate of HSV-2 seropositivity declined
in the United States from 21% in 19881994 to 17% in
19992004, and rate of HSV-1 seropositivity declined
from 62% to 58% during the same period.6
Although most patients infected with HSV-1 or
HSV-2 are asymptomatic, they still can transmit the
virus. Studies using DNA polymerase chain reaction
(PCR) assays show that rates of detecting HSV-2 DNA
in genital secretions of people who have never recog-
nized herpes outbreaks (asymptomatic persons) are
similar to the rates of shedding viral DNA in people
who have experienced symptomatic genital herpes
but who are not symptomatic at the moment of test-
ing (subclinical shedding).7 In one study, 21% of geni-
tal swabs were positive for HSV-2 by PCR and 12% of
oral swabs were positive for HSV-1 PCR in HSV-2 and
HSV-1 seropositive persons, respectively.8 It is esti-
mated that more than 70% of transmission of HSV-2
is associated with asymptomatic and subclinical reac-
tivation and shedding. The rate of transmission is no
higher is persons with frequent symptomatic recur-
rences than those with infrequent recurrences.9 The
average risk of transmission for couples discordant for
genital herpes (i.e., one partner has genital herpes and
the other does not) varies from 5% to 10% per year.10,11
As with other sexually transmitted infections, the rate
of acquisition of HSV-2 infection is higher for women
than for men (6.8 vs. 4.4 cases per 100 person-years;
2367
31 relative risk, 1.55). Asymptomatic HSV-2 infection is
more common among men and persons who are also
seropositive for HSV-1, suggesting that prior infection
with HSV-1 reduces ones likelihood of experiencing
symptomatic HSV-2 infection.12 Studies have shown
that genital HSV infections significantly increase the
risk for acquisition and transmission of human immu-
nodeficiency virus (HIV). Randomized trials with
acyclovir reduced the frequency of genital ulcers and
slightly reduced HIV viral loads, but did not reduce
transmission of HIV.13,14
ETIOLOGY AND PATHOGENESIS
Section 31
THE VIRUS
HSV-1 and HSV-2 are members of the Herpesviridae
family, a group of lipid-enveloped double-stranded
DNA viruses. Both serotypes of HSV are members of
::
the -Herpesviridae virus subfamily. -Herpesviruses
Viral and Rickettsial Diseases
infect multiple cell types in culture, grow rapidly, and
efficiently destroy the host cells. Infection in the natural
host is characterized by lesions in the epidermis, often
involving mucosal surfaces, with spread of virus to the
nervous system and establishment of latent infections
in neurons, from which virus periodically reactivates.
HSV-1 and HSV-2 have a high degree of genetic and
antigenic homology. An analysis of herpesvirus phy-
logeny estimated that the two HSV types diverged
from an ancestral protoherpesvirus approximately
8 million years ago.15
Herpesvirus replication is a carefully regulated pro-
cess. Shortly after infection, immediate-early genes are
transcribed whose proteins upregulate expression of
early proteins that are required for genome replication.
The late [HSV-2HSV] genes encode virion structural
components including the glycoproteins.
In vivo, HSV infections can be divided into three
stages: (1) acute infection, (2) establishment and main-
tenance of the latency, and (3) reactivation of virus.
During acute infection, virus replicates at the site of
inoculation on mucocutaneous surfaces, resulting in
primary lesions from which virus rapidly spreads to
infect sensory nerve terminals, where it travels by ret-
rograde axonal transport to neuronal nuclei in regional
sensory ganglia. In a subset of infected neurons, a
latent infection is established in which viral DNA is
maintained as an episome and HSV gene expression
is severely restricted: of all of the viral genes, only one
is abundantly transcribed during latency. In the last
stage, replication reactivates with concomitant antero-
grade axonal transport of newly assembled virus to a
peripheral site, at or near the original portal of entry
(see eFig. 193-0.1 in online edition).
HSV-1 reactivates most efficiently and frequently
from trigeminal ganglia, whereas HSV-2 reactivates
primarily from sacral ganglia. The rate of reactiva-
tion of HSV appears to be influenced by the quantity
of latent viral DNA in the ganglia.16 Reactivation is
induced in experimentally infected animals by expo-
sure to ultraviolet irradiation, by hyperthermia, by
2368 local trauma, and by other physiologic stressors.
IMMUNE RESPONSE
Host immunity to HSV clearly influences the risk of
acquiring the infection, the severity of disease, and the
frequency of recurrences. The risk of severe HSV dis-
ease and the recurrence rate correlates with the level of
cellular immune competence of the host. Patients with
mild decreases in cellular immunity may experience
only an increased number of recurrences and a slower
resolution of lesions, whereas severely compromised
patients are more likely to develop disseminated,
chronic, or drug-resistant infections.
Studies of humans and mice have implicated a
role for both CD8+ and CD4+ T lymphocyte subsets,
natural killer cells, and inflammatory cytokines like
interferon- in mediating protection against HSV.
However, the contribution of each cell subset and
cytokine in the control of HSV infection has not been
clearly defined. Innate immunity is also important and
polymorphisms in TLR2 are associated with increased
rates of genital lesions in seropositive persons.17
Patients with defects in humoral immunity have
no increase in HSV disease severity, but the humoral
immune response is important in reducing virus titers
at the site of inoculation and in regional neural tissues
during primary infection. Animals are effectively pro-
tected from disseminated and neurologic disease by
passive transfer of polyclonal or monoclonal antibod-
ies and by antibody responses elicited actively through
vaccination. Moreover, the transfer of HSV-specific
antibodies from the mother to the child is a key factor
in protecting against neonatal herpes.
The mechanisms of immunity required to sustain
latency and limit reactivation of HSV are less clear.
There is evidence that constant immune surveillance
and engagement are required to maintain latency,
mainly by HSV-specific CD8+ lymphocytes and low
levels of viral proteins produced in neurons.18 T cells
reactive to HSV-1 are clustered around latently infected
neurons in ganglia from HSV-1 seropositive persons.19
HSV-specific CD8+ lymphocytes localize to site of reac-
tivation and persist in the skin for weeks after lesions
are cleared.20
CLINICAL FINDINGS
The clinical manifestations of HSV infection depend
on the site of infection and, as indicated in Immune
Response (above), the immune status of the host. Pri-
mary infections with HSV, namely those that develop
in persons without preexisting immunity to either
HSV-1 or HSV-2, are usually more severe, frequently
with systemic signs and symptoms, and they have a
higher rate of complications, than recurrent episodes.
OROFACIAL INFECTIONS
Herpetic gingivostomatitis (Fig. 193-1) and pharyngitis
are most commonly associated with a primary HSV-1
infection. The symptoms of primary oral herpes may
resemble those of aphthous stomatitis and include

Figure 193-1 Primary herpetic gingivostomatitis. (Used
with permission from Clyde S. Crumpacker, MD.)
ulcerative lesions involving the hard and soft palate,
tongue, and buccal mucosa, as well as neighboring
facial areas. Patients with pharyngitis exhibit ulcer-
ative and exudative lesions of the posterior pharynx
that can be difficult to differentiate from streptococcal
pharyngitis. Other common symptoms are fever, mal-
aise, salivation, myalgias, pain on swallowing, irrita-
bility, and cervical adenopathy.
Reactivation of virus from these primary infections
involves the perioral facial area, mainly the lips, with
the outer one-third of the lower lip being the most
commonly affected (Fig. 193-2 and see eFig. 193-2.1
in online edition). Other facial locations include the
nose, chin, and cheek, and account for less than 10%
of the cases (Fig. 193-3). Two-thirds of labial lesions
involve the vermilion border, whereas the rest occur
at the junction of the border with the skin. In patients
with frequent recurrences, lesions may differ slightly
in location with each episode. Immunocompetent
patients tend not to experience recurrent intraoral
lesions, but can present with clusters of tiny vesicles
and ulcers, or linear fissures on the gingivae and ante-
rior hard palate that are mildly symptomatic. Prodro-
mal symptoms precede herpes labialis in 45%60% of
Figure 193-2 Herpes simplex virus infection: recurrent
herpes labialis.
31
Chapter 193
::
Figure 193-3 Recurrent facial herpes simplex with
Herpes Simplex
grouped vesicles and crusting. (Used with permission
from Clyde S. Crumpacker, MD.)
episodes. Patients experience pain, burning, or itch-
ing at the site of the subsequent eruption. Even in the
immunocompetent patient, the severity of recurrent
herpes labialis is extremely variable and may vary
from that of prodromal symptoms alone without the
subsequent development of lesions (aborted episodes)
to extensive disease induced by severe local sunburn.
The progression of the classical herpes lesions has
been divided according to the following stages based
on their features: prodromal, erythema, and papule
(the developmental stages); vesicle, ulcer, and hard
crust (disease stages); followed by dry flaking and
residual swelling (resolution stages). The lesions usu-
ally resolve within 515 days.
Trigger factors for oral herpes recurrences include
emotional stress, illness, exposure to sun, trauma,
fatigue, menses, chapped lips, and the season of
the year.21 Other well-documented triggers include
exposure to ultraviolet irradiation, trigeminal nerve
surgery, oral trauma, epidural administration of mor-
phine, and abrasive, laser, and chemical facial cosmetic
procedures. The exact mechanism by which these
diverse factors trigger HSV reactivation is unknown.
HSV-2 causes a primary orofacial infection that is
indistinguishable from that associated with HSV-1
except that it is usually in adolescents and young
adults and following genitaloral contact. Moreover,
HSV-2 orolabial infections are 120 times less likely to
reactivate than is orolabial HSV-1 disease. For the dif-
ferential diagnosis of orofacial herpes see Box 193-1.
GENITAL INFECTION
Genital herpes is the major clinical presentation of
HSV-2 infection, but it may also result from HSV-1
in 10%40% of the cases, primarily following oral
genital contact.22 Because of their epidemiology, 2369
31 Box 193-1 Differential Diagnosis
HSV-1 genital infection who develop frequent genital
herpes recurrences should be tested for HSV-2 infec-
of Orolabial and Genital Herpes tion.23 Viremia occurs in about 25% of persons during
primary genital herpes.24
Differences from Orolabial The clinical course of acute first-episode genital her-
Disease Herpes pes among patients with HSV-1 and HSV-2 infections
Aphthous ulcers Not preceded by vesicles, is similar. These infections are associated with exten-
only on mucosa sive genital lesions in different stages of evolution,
Syphilis Painless, not preceded by including vesicles, pustules, and erythematous ulcers
that may require 23 weeks to resolve (Fig. 193-4). In
vesicles
males, lesions commonly occur on the glans penis or
Herpangina Posterior portion of mouth
the penile shaft; in females, lesions may involve the
(soft palate, tonsils)
vulva, perineum, buttocks, vagina, or cervix. There is
Stevens Johnson Disseminated lesions
accompanying pain, itching, dysuria, vaginal and ure-
syndrome thral discharge, and tender inguinal lymphadenopa-
Section 31

Differences from Genital thy. Systemic signs and symptoms are common and
Disease Herpes include fever, headache, malaise, and myalgias. Her-
Chancroid Deep ulceration with petic sacral radiculomyelitis, with urinary retention,
neuralgias, and constipation, can occur. HSV cervici-
exudate
tis occurs in more than 80% of women with primary
::

Syphilis Painless, not preceded by

infection. It can present as purulent or bloody vaginal
vesicles
Viral and Rickettsial Diseases

discharge, and examination reveals areas of diffuse or

Lymphogranuloma Painless ulcer, unimpressive
focal friability and redness, extensive ulcerative lesions
venereum primary lesions of the exocervix, or, rarely, necrotic cervicitis. Cervi-
Granuloma inguinale Painless ulcer, exuberant cal discharge is usually mucoid, but it is occasionally
lesions mucopurulent.
The rates of recurrence for genital HSV-2 infections
vary greatly among individuals and over time within
the same individual. Infections caused by HSV-2 reac-
acquisition of HSV-1 in a person with prior HSV-2 tivate approximately 16 times more frequently than
infection is unusual, but HSV-2 acquisition in the pres- HSV-1 genital infections, and average 34 times per
ence of previous HSV-1 infection is common, and infec- year, but may appear virtually weekly.3 Recurrences
tion of the genital tract with both HSV-1 and HSV-2 tend to be more frequent in the first months to years
has been described. Patients with previously known after first infection. The classical clinical manifestations

A B

Figure 193-4 A. Primary genital herpes with vesicles. (Used with permission from Clyde S. Crumpacker, MD.) B. Primary
2370 herpetic vulvitis.
 31

Chapter 193
A B

::
Figure 193-5 A. Genital herpes: recurrent infection of the penis. Group of vesicles with early central crusting on a red

Herpes Simplex
base arising on the shaft of the penis. This textbook presentation, however, is much less common than small asymptom-
atic erosions or fissures. B. Genital herpes: recurrent vulvar infection. Large, painful erosions on the labia. Extensive lesions
such as these are uncommon in recurrent genital herpes in an otherwise healthy individual.

of recurrent HSV-2 infection include multiple small but
grouped vesicular lesions in the genital area (Fig. 193-
5), but it can occur anywhere in the perigenital region,
including the abdomen, groin, buttocks, and thighs
(Fig. 193-6), and the lesions may recur at the same site
or change location. The recurrence of genital lesions
may be heralded by a prodrome of tenderness, itch-
ing, burning, or tingling, and the outbreaks are less
severe than primary infection. Without treatment, the
lesions usually heal in 610 days. Herpetic cervicitis is
less common in recurrent disease, occurring in 12% of
patients. It may present without external lesions. Signs
and symptoms that are less classical for genital HSV
infection, and which may divert one from the correct
diagnosis include small erythematous lesions, fissures,
pruritus, and urinary symptoms. HSV can cause ure-
Figure 193-6 Recurrent genital herpes on the abdomen
(zosteriform herpes simplex).
thritis, usually manifested only as a clear mucoid dis-
charge, dysuria, and frequency. Occasionally, HSV can
be associated with endometritis, salpingitis, or pros-
tatitis. Symptomatic or asymptomatic rectal and peri-
anal infections are common. Herpetic proctitis presents
with anorectal pain, anorectal discharge, tenesmus, and
constipation, with ulcerative lesions of the distal rectal
mucosa. Genital herpes can recur at nongenital sites as
well. For the differential diagnosis of genital herpes, see
Box 193-1.
OTHER CUTANEOUS INFECTIONS
HSV can infect any skin site (Fig. 193-6). The common
theme among virtually all of these cutaneous presenta-
tions is the requirement that virus has penetrated oth-
erwise normal and well-keratinized tissues. Herpetic
whitlow (Fig. 193-7) is infection of the fingers by HSV
acquired by direct inoculation or by direct spread from
mucosal sites at the time of primary infection. Thus, a
typical presentation of whitlow would be in children
who suck their fingers during a primary gingivosto-
matitis outbreak. It is also a well-documented occu-
pational hazard for medical personnel. It is usually
caused by HSV-1, but HSV-2 whitlow may develop
as a manifestation of primary inoculation following
manualgenital contact with an infected partner. The
infected region becomes erythematous and edema-
tous. Lesions are usually present at the fingertip and
can be pustular and very painful. Fever and local
lymphadenopathy are common. Whitlow is often mis-
diagnosed as a bacterial paronychial infection, but the
surgical drainage, often needed for a bacterial infec-
tion, is unnecessary and potentially harmful, while
antiviral therapy speeds healing. Whitlow may recur. 2371
31
Section 31
::
Viral and Rickettsial Diseases
Figure 193-7 Herpes simplex virus infection: herpetic
whitlow. Painful, grouped, confluent vesicles on an ery-
thematous edematous base on the distal finger were the
first (and presumed primary) symptomatic infection.
Cutaneous herpes can be transmitted between ath-
letes involved in contact sports, such as wrestling
(herpes gladiatorum) and rugby (herpes rugbiaforum
or scrum pox), and may occur as outbreaks or small
epidemics among team members. In these instances,
multiple herpetic lesions may appear across the tho-
rax, ears, face, arms, and hands, in which infection is
facilitated by trauma to the normally keratinized skin
during sport activities (Fig. 193-8A). Concomitant ocu-
lar herpes can occur.
A B
Figure 193-8 A. Herpes simplex gladiatorum with lesions on the neck. B. Herpes simplex virus infection: eczema herpe-
ticum on face. Confluent and discrete crusted erosions associated with erythema and edema of the face of a man with
2372 atopic dermatitis.
Eczema herpeticum (Kaposi varicelliform eruption;
Fig. 193-8B and eFig. 193-8.1 in online edition) results
from widespread infection following inoculation of
virus to skin damaged by eczema. It is usually a mani-
festation of primary HSV-1 infection in a child with
atopic dermatitis, and the expression of cathelicidins in
the skin may be a factor in controlling susceptibility to
eczema herpeticum in these patients.25 Mycosis fungoi-
des, Szary syndrome, Darier disease, various bullous
diseases of the skin (particularly if patients are receiv-
ing immunosuppressive therapy), and burns of second
or third degree can also be complicated by cutaneous
dissemination of HSV. The severity of eczema herpe-
ticum ranges from mild to fatal, with mortality rates
of up to 10% being reported before antiviral therapy
was available. Mortality was usually primarily caused
by bacterial superinfection and bacteremia. Common
pathogens include Staphylococcus aureus, Streptococcus,
and Pseudomonas. In a typical severe primary attack,
several days after exposure vesicles develop in large
numbers over areas of active or recently healed atopic
dermatitis, particularly the face, and continue to appear
in crops for several more days. The vesicles become
pustular and markedly umbilicated. Patients com-
monly have high fever and adenopathy. Viremia with
infection of internal organs can be fatal. Recurrences
are usually far milder than these first infections. Arriv-
ing at the correct diagnosis can be delayed because of
secondary impetigo involving the lesions, but it always
should be considered in children with infected eczema,
particularly if the child is more systemically ill than one
might anticipate with impetigo. Eczema herpeticum
of the young infant is a medical emergency, and early
treatment with acyclovir can prove lifesaving.
Recurrent HSV infection is the most common pre-
cipitating event in cases of recurrent erythema mul-
tiforme (see Chapter 39). HSV-associated erythema
multiforme is usually an acute, self-limited, recurrent
disease. The duration of the disease is usually about
3 weeks. The lesions are usually disseminated and
symmetric, occurring on acral extremities and the face,
and there is grouping of the lesions over the elbow
and knees, as well as nail fold involvement. Muco-
sal involvement is usually mild and restricted to the
mouth. Constitutional symptoms are rare, and the skin
lesions heal without scarring.
LABORATORY TESTS
The method of choice for diagnosis of HSV infec-
tion depends on the clinical presentation. In many
instances, the history and clinical findings may
be sufficient, but the social, emotional, and thera-
peutic implications of a diagnosis dictate that it be
confirmed by laboratory testing when possible. For
patients with lesions, virus can be isolated in cell
culture. In culture, HSV causes typical cytopathic
effects, and most specimens will prove positive
within 4896 hours after inoculation. The sensitivity
of the culture depends on the quantity of the virus in
the specimen. Even in the most experienced centers,
only approximately 60%70% of fresh genital lesions
are culture-positive. Isolation of the virus is most
successful when lesions are cultured during their
vesicular stage and when specimens are taken from
immunocompromised patients or from patients suf-
fering from a primary infection.
PCR is more sensitive than viral isolation and has
become the preferred method for diagnosis. PCR has
been extensively used for the diagnosis of central ner-
vous system infections and in neonatal herpes. It is
also useful for the detection of HSV in late-stage ulcer-
ative lesions. Both viral culture and PCR assays enable
typing of the isolate as HSV-1 or HSV-2. This informa-
tion helps to predict the frequency of reactivation after
a first-episode of HSV infection.
Direct fluorescent antibody staining of lesion scrap-
ings and antigen detection assays can also be used but
TABLE 193-1
Classification of Herpes Simplex Infections According to Viral Isolation and Paired
Serologic Test Results
Virus
Classification Isolated
Primary HSV-1 HSV-1
Primary HSV-2 HSV-2
Primary HSV-1 plus previous HSV-1
HSV-2 infectiona
Primary HSV-2 plus previous HSV-2
HSV-1 infection
Recurrent HSV-1 HSV-1
Recurrent HSV-2 HSV-2
HSV = herpes simplex virus; = negative; + = positive.
a
Rare.
31
Figure 193-9 Herpes simplex virus: positive Tzanck smear.
A giant, multinucleated keratinocyte on a Giemsa-stained
Chapter 193
smear obtained from a vesicle base. Compare size of the
giant cell to that of neutrophils also seen in this smear.
Another smaller multinucleated acantholytic keratinocyte
is seen as well as acantholytic keratinocytes. Identical find-
ings are present in lesions caused by varicella-zoster virus.
::
sensitivity is lower than viral culture.26 The Tzanck
smear can be helpful in the rapid diagnosis of herpes-
Herpes Simplex
virus infections, but it is less sensitive than culture and
staining with fluorescent antibody, with positive results
in fewer than 40% of culture-proven cases. It is per-
formed by scraping the base of a freshly ruptured vesi-
cle and staining the slides with Giemsa or Wright stain
(the Papanicolaou staining method can also be used),
followed by examination for the multinucleated giant
cells that are diagnostic of herpetic infection (Fig. 193-9).
Both HSV and varicella-zoster virus (VZV) will cause
these changes. In skin biopsy specimens, epithelial cells
are enlarged, swollen, and often separated. Multinucle-
ated cells with intranuclear eosinophilic inclusion bod-
ies (Cowdry type A inclusions) can be seen.
Serologic detection of antibodies to HSV can be help-
ful in certain settings, but the results are often misinter-
preted. Its main function is in differentiating a primary
episode from a recurrent infection (Table 193-1). A pos-
itive serologic test result can be useful in patients with
Serology (Acute) Serology (Convalescent)
HSV-1 HSV-2 HSV-1 HSV-2
+
+
+ + +
+ + +
+ or + + or +
or + + or + +
2373
31 recurrent, genital lesions that are not present at times
of examination and, therefore, a positive culture can-
not be obtained. Serologic testing can also be helpful
for counseling patients with initial episodes of disease
and their partners, especially during pregnancy, and
in counseling partners of patients with genital herpes
about their risk of acquiring HSV.
Type-specific serologic assays based on antigenic
differences between HSV-1 and HSV-2 glycoprotein
G, are available.27 These tests should be used by prac-
titioners who are prepared to counsel patients about
the meaning of the test results in terms of the natural
history of the disease, available treatment regimens,
disease transmission, and the emotional and social
implications of the diagnosis.28
Section 31

COMPLICATIONS
IMMUNOCOMPROMISED HOST
::
Viral and Rickettsial Diseases

All manifestations of HSV infection seen in the immu-

nocompetent host can also be seen in immunocom-
promised patients but they are usually more severe,
more extensive, and difficult to treat; for many of
them, recurrences are more frequent as well. Patients
with defects of T cell immunity, such as those with
AIDS or transplant recipients, are at particular risk for
progressive mucocutaneous or visceral infections, but
the degree of dissemination depends on the level of
immunodeficiency of the host. Recurrent and persistent
ulcerative HSV lesions are among the most common
and defining opportunistic infections in patients with
acquired immunodeficiency syndrome. Genital her-
pes is very common in patients with HIV and can be
persistent and severe. Oropharyngeal HSV in immu-
nocompromised patients can present with widespread
involvement of skin (Fig. 193-10), the mucosa, and
extremely painful, friable, hemorrhagic, and necrotic
lesions, similar to mucositis caused by cytotoxic
agents. The lesions can spread locally to involve the
esophagus. Esophagitis presents with odynophagia,
dysphagia, substernal pain, and multiple ulcerative
lesions. Esophagitis can also arise directly by reac-
tivation of HSV and its spread to the esophagus via
the vagus nerve. Tracheobronchitis can also occur by
spreading of the virus from oropharyngeal HSV.
HSV can reactivate from visceral ganglia of the auto-
nomic nervous system or disseminate hematogenously
to other visceral organs (causing pneumonitis, hepati-
tis, pancreatitis, or meningitis) and other portions of
the gastrointestinal tract, as well as causing adrenal
necrosis. Most of these severe infections are caused by
HSV-1, but HSV-2 can do so as well. Few are ever diag-
nosed except at autopsy.
OCULAR INFECTIONS
HSV is a leading cause of recurrent keratoconjunctivi-
tis and it is associated with corneal opacification and
visual loss. It is usually caused by HSV-1, except in
2374
Figure 193-10 Herpes simplex virus infection: chronic
ulcer in an immunocompromised host. Multiple, slowly
spreading, deep ulcers with central necrosis and hemor-
rhagic crusts on the lips, cheeks, and nose of a woman
with leukemia.
neonates in whom HSV-2 is more prevalent. The major-
ity of HSV eye disease is caused by reactivation of the
virus in the trigeminal ganglia, but primary infections
of the eye can also occur. Usually, the initial manifesta-
tion of herpetic eye disease is a superficial infection of
the eyelids and conjunctiva (blepharoconjunctivitis),
or corneal surface (dendritic or geographic epithelial
ulcer with pain and blurred vision). Deeper involve-
ment of the cornea (stromal keratitis) or anterior uvea
(iritis) represents more serious forms of the disease and
can cause permanent visual loss. Acute retinal necrosis
is a rare but rapidly progressive disease characterized
by retinal arteriolar sheathing, uveitis, and peripheral
retinal opacification with variable pain and visual loss.
Bilateral involvement may occur, and retinal detach-
ment is common. It is usually associated with HSV-1
infection, but HSV-2 retinitis has been described, and
VZV causes a similar process.29
NEUROLOGIC DISORDERS
All HSV infections involve the nervous system, as neu-
rons are the sole proven site of virus latency. Neuro-
logic manifestations of HSV infections, however, are
not universal, but highly variable in their presentation
and severity. HSV meningitis is manifested by head-
ache, fever, stiff neck, and mild photophobia, with lym-
phocytic pleocytosis in the cerebrospinal fluid (CSF).
Most cases result from HSV-2 infection.30 It resolves
spontaneously in 27 days. It is usually seen in asso-
ciation with primary genital HSV-2 infection. Recur-
rent lymphocytic meningitis (Mollaret meningitis)
is associated with HSV-2 reactivation, often without
symptomatic genital disease. Involvement of the sacral
nerves with autonomic nervous system dysfunction,
31
numbness, pelvic pain, tingling, urinary retention,
constipation, and CSF pleocytosis have been reported
in association with HSV infection. Symptoms usually
resolve in a few days, but in some cases, the neurologic
residua take weeks to months to disappear, occasion-
ally becoming permanent. Rare cases of transverse
myelitis and Guillain-Barr syndrome after HSV infec-
tion have been reported. Bell palsy is an acute, periph-
eral facial paresis of unknown cause and is thought to
result from inflammation and subsequent mechanical
compression of the facial nerve in the temporal bone.
Reactivation of HSV and VZV are implicated in the
pathogenesis of the disease.31

Chapter 193
HSV encephalitis is the most commonly identi-
fied acute, sporadic viral encephalitis in the United
States, accounting for 10%20% of all cases. Nearly
all of the cases arising after the neonatal period (see
Section Neonatal Herpes) are caused by HSV-1.
HSV encephalitis usually presents with acute onset

::
of focal neurologic symptoms and fever. Involvement

of the temporal lobe is a characteristic feature of this
disease, but overall, it is difficult to differentiate HSV
encephalitis clinically from other viral encephalitides.
PCR of the CSF for HSV DNA is the most sensitive
noninvasive technique to help in the diagnosis, but it
can occasionally be negative very early in the course of
the disease.32 Patients with presumed HSV encephali-
tis should be treated empirically with intravenous acy-
clovir until the diagnosis is confirmed or an alternative
diagnosis is made. However, even with therapy, neu-
rologic sequelae are frequent.33
NEONATAL HERPES
The neonate is a special category of immunodeficient
host. The incidence of neonatal herpes varies from 1
case per 12,500 to 1 per 1,700 live births.34 The category
of maternal infection plays a significant role in defin-
ing the risk of neonatal herpes. Primary genital herpes
is associated with a risk of neonatal infection of 25%
50% for vaginally delivered babies, and accounts for
50%80% of cases of neonatal HSV infection. In con-
trast, recurrent maternal infection is associated with a
risk of transmission of less than 3%, and transplacental
antibodies are likely to play a role in decreasing the
risk of infection.35 Other risk factors for development
of neonatal herpes include vaginal delivery, presence
of cervical HSV infection, use of invasive monitors,
and isolation of HSV from the genital tract.36 Prolonged
rupture of the membranes is also a risk factor.
Neonatal herpes infections manifest in one of the
three forms: (1) skin, eye, and mouth involvement; (2)
encephalitis; or (3) disseminated disease (Fig. 193-11).
The latter two forms account for more than 50% of cases
of neonatal herpes. It is important to remember that
more than 20% of neonates with neurologic and dis-
seminated disease do not develop cutaneous vesicles.
Without therapy, the overall mortality of neonatal her-
pes is 65%, and fewer than 10% of untreated neonates
Herpes Simplex
Figure 193-11 Neonatal herpes simplex virus 2.
with central nervous system infection will develop
normally. With current therapeutic modalities, most
babies with skin, eye, and mouth disease survive and
have normal development at 1 year. For treated babies
with encephalitis, mortality is 6%, with about 30%
developing normally after 1 year. For babies with dis-
seminated disease, mortality is 30%, with about 80%
of the survivors apparently developing normally after
1 year.34
TREATMENT
All sexually active persons should be educated regard-
ing the nature and risks of acquiring and transmitting
sexually transmitted infections, including HSV. Studies
show that about one-half of the patients with asymp-
tomatic HSV-2 infection have mild, unrecognized dis-
ease and can be taught to recognize their symptoms
and signs of genital herpes. Also, patients should be
counseled regarding safer sex practices. It must be
emphasized that the majority of transmission occurs
in asymptomatic phases and from people who have no
classical lesions. Patients with genital herpes should
be counseled to refrain from sexual intercourse during
outbreaks and for 12 days after and to use condoms
between outbreaks. Suppressive antiviral therapy is
also an option for individuals concerned about trans-
mission to a partner (see Section Antiviral Therapy
under Prevention).
Pregnant women who are known to have genital
herpes should be reassured that the risk of trans-
mitting herpes to the baby during childbirth is
extremely low. Recommendations for the manage-
ment of pregnant women with recurrent genital
herpes include clinical evaluation at delivery, with
2375
31 delivery by Cesarean section indicated if there are
signs and symptoms of active infection (including
prodrome). But Cesarean section delivery may not
reliably prevent neonatal HSV infection when mem-
branes are ruptured for long periods (24 hours).
Women with primary HSV infection during preg-
nancy should be treated with antiviral therapy. For
women at or beyond 36 weeks of gestation who
are at risk for recurrent HSV infection, suppressive
antiviral therapy has been recommended, (1) as this
decreases viral shedding, the incidence of active
lesions near term, and the need of Cesarean delivery
due to HSV.37,38 Close follow-up, sequential70 PCR
or cultures for HSV of infants born to seropositive
mothers who are shedding virus at the time of deliv-
Section 31
ery, prophylactic therapy with intravenous acyclovir
for infants born to mother with primary infection,
and intravenous acyclovir if HSV is detected in
infants of seropositive mothers have also been sug-
gested.34
::
Women who are known by history and serologic
Viral and Rickettsial Diseases
tests not to have genital herpes should be counseled
about signs and symptoms of HSV and how to avoid
acquiring the infection during pregnancy. Serology is
helpful in counseling a couple in which the male part-
ner has recurrent genital herpes and the pregnant wife
is susceptible.
ANTIVIRAL THERAPY
(See Chapter 231)
Many HSV infections require no specific treatment
at all. Keeping the lesions clean and dry while they
heal by themselves may be all that is required. Treat-
ment is warranted for infections that are likely to prove
protracted, highly symptomatic, or complicated. Acy-
clovir, an acyclic guanosine analogue, has a highly
favorable therapeutic index because of its preferential
activation in infected cells and preferential inhibition of
the viral DNA polymerase. It must be phosphorylated
to be active, and it requires the viral thymidine kinase
(TK) for initial phosphorylation. Acyclovir inhibits
HSV-1 and HSV-2 replication by 50% at a concentration
of 0.1 and 0.3 g/mL (range, 0.019.9 g/mL), respec-
tively, but is toxic at concentrations of >30 g/mL. Any
strain that requires more than 3 g/mL of acyclovir to
be inhibited is said to be relatively drug resistant.
Valacyclovir, the l-valyl ester of acyclovir, is an
oral prodrug of acyclovir that achieves three- to five-
fold higher bioavailability after oral administration,
and it can be used in a more convenient dosage regi-
men. Famciclovir is the well-absorbed oral form of
the related guanosine analogue penciclovir. Similar
to acyclovir, famciclovir is converted by phosphoryla-
tion to its active metabolite penciclovir triphosphate.
The efficacy and adverse effect profile of famciclovir is
comparable to that of acyclovir. Penciclovir 1% cream
is approved by the U.S. Food and Drug Administra-
tion (FDA) for the treatment of herpes simplex labia-
lis. Docosanol 10% cream is approved by the FDA for
over-the-counter treatment of recurrent herpes labia-
2376 lis. Docosanol is a long-chain saturated alcohol that
inhibits entry of lipid-enveloped virus into the cell.
It decreased the healing time by 18 hours when com-
pared with placebo.39
The current recommendations for antiviral
treatment depend on the clinical disease, on host
immune status, and whether one is treating a pri-
mary or recurrent episode or considering suppres-
sive therapy (Boxes 193-2, 193-3, 193-4, and 193-5).84
For disseminated or severe herpes infections, the
treatment of choice remains intravenous acyclovir
510 mg/kg every 8 hours. Some experts use acyclovir
15 mg/kg intravenously every 8 hours for life-threat-
ening HSV infection, including encephalitis. The dose
of intravenous acyclovir for neonatal herpes is 20 mg/
kg per dose given every 8 hours.
For first episodes of genital HSV-2 infections, oral
acyclovir, famciclovir, and valacyclovir all speed the
healing and resolution of symptoms, and decrease
viral shedding. When compared with placebo, acy-
clovir decreases time of healing from 16 to 12 days,
the duration of pain from 7 to 5 days, and the dura-
tion of constitutional symptoms from 6 to 3 days.51
Valacyclovir was compared with acyclovir in the
treatment of primary episodes and shown to be
equivalent.52 Antiviral treatment of initial herpes
episodes does not decrease subsequent recurrences,
probably because HSV establishes latent infection
within hours after inoculation and days before symp-
toms evolve.
Treatment of recurrent episodes of genital herpes
with famciclovir, acyclovir, or valacyclovir has been
shown to reduce the time of healing from about 7 to
5 days, time of cessation of viral shedding from 4 to
2 days, and duration of symptoms from 4 to 3 days
when compared with placebo. Valacyclovir and acy-
clovir are equivalent54,56; valacyclovir was similar to
famciclovir in one study,57 but slightly superior to fam-
ciclovir to suppress genital herpes in another study.67
A regimen of patient-initiated, 1-day famciclovir
1,000 mg twice daily was not different from placebo
in immunocompetent black adults in a recent study,
but this finding warrants further investigation.85 For
persons with frequent or complicated genital recur-
rences, long-term suppressive therapy with acyclovir
or its analogues is the most effective management
strategy.71,86,87 Suppressive therapy was effective dur-
ing the first year after acquisition of genital herpes.69,70
Suppressive therapy reduces the rate of shedding in
healthy persons and those with HIV.60,70,88,89 Suppres-
sive therapy with valacyclovir was more effective
to reduce the burden of genital herpes disease than
episodic therapy.90 Because genital herpes is not pro-
gressive in the normal host and because the rate of
recurrences varies over time and may decrease after
some years, it is wise to recommend a holiday from
treatment every year or so to reassess the persons
continuing need for treatment.
The use of antiviral suppressive therapy during
the late phase of pregnancy to avoid neonatal her-
pes has also been advocated, but a formal study of
the approach would require a very large number of
participants because of the rare incidence of neona-
tal herpes. A more achievable goal is to decrease the
 Box 193-2 Recommended Regimens for the Treatment of Orofacial Herpes
31
Simplex Infections
Acceptable Regimen Alternativesa

Disease Adults Pediatricb Duration Comments

Primary infec- Acyclovir, 200 mg orally five 15 mg/kg of acy- 710 days or until IV acyclovir for
tion times a day. clovir orally five resolution of severely ill individuals.
Acyclovir, 400 mg orally three times a day.40 symptoms. No studies have been
times a day. done in adults: regi-
Valacyclovir, 1,000 mg orally mens are extrapolated
two times a day. from their effective-
Famciclovir, 250 mg orally ness in primary geni-

Chapter 193
three times a day. tal herpes.
Recurrent infec- Topical penciclovir, 1% cream 45 days or until Generally not war-
tion: episodic q2h while awake.41 lesions are healed. ranted.
treatment Topical docosanol 10% cream Valacyclovir and
five times a day.39 famciclovir were

::
Acyclovir, 400 mg orally five used for only 1

Herpes Simplex
times a day.42 day.
Famciclovir, 500 mg orally two
or three times a day.43,44
Valacyclovir, 2,000 mg orally
twice a day for 1 day.45
Famciclovir, 1,500 mg single
dose or 750 mg twice a day for
1 day.46
Recurrent infec- Acyclovir, 400 mg orally twice Start just before and
tion: prophy- a day.47 during precipitat-
laxis ing event, such as
intensive ultraviolet
exposure.
Recurrent Acyclovir, 400 mg orally twice There are no pedi-
infection: sup- a day.48 atric studies, but
pression of con- Valacyclovir 500 mg once a children with con-
firmed frequent day.49 firmed frequent
recurrences Valacyclovir 1,000 mg once a recurrences may
day.50 benefit from sup-
pressive oral acy-
clovir therapy.
a
The doses are for patients with normal renal function.
b
Oral dosage of acyclovir in children should not exceed 80 mg/kg/day. Children 40 kg and above should receive the adult dose.
Note: Neither valacyclovir nor famciclovir is approved by the US Food and Drug Administration for use in children.

need for Cesarean deliveries caused by herpes recur-
rences during labor. Studies have shown that antivi-
ral therapy in late pregnancy (beginning at 36 weeks)
prevent clinical recurrences, Cesarean sections due to
genital herpes, and the risk of HSV viral shedding at
delivery.91
Orolabial HSV infections warrant antiviral treat-
ment less often than do the genital infections. Pri-
mary HSV gingivostomatitis should be treated with
oral acyclovir. The pediatric dose is 15 mg/kg of
acyclovir suspension orally five times a day for 7
days. When it is started within 3 days of onset of the
disease, this regimen decreases the duration of oral
and extraoral lesions, fever, and eating and drink-
ing difficulties. Valacyclovir and famciclovir may be
equally effective, but they have not been studied in
this setting and are not currently approved for use in
children. Severely ill children may need to be hospi-
talized for hydration, and intravenous acyclovir may
be necessary.
Treatment of recurrent herpes labialis with anti-
viral drugs in immunocompetent hosts has shown 2377
31 Box 193-3 Recommended Regimens for the Treatment of Genital Herpes
Simplex Infections
Acceptable Regimen Alternativesa

Disease Adults Pediatricb Duration Comments

Primary Acyclovir, 200 mg orally five times a Acyclovir, 4080 710 days or
infection day.51 mg/kg/ day clinical resolu-
Acyclovir, 400 mg orally three times a orally divided tion occurs.
day.52 in three to four
Valacyclovir, 1,000 mg orally twice a doses (maximum
day.52 1 g/d).53
Famciclovir, 250 mg orally three times
Section 31

a day.
Recurrent Acyclovir, 400 mg orally three times a For children 12 510 days or
infection day. years of age: until clinical res-
Acyclovir, 200 mg orally five times a acyclovir, 200 mg olution occurs.
day.54 orally five times
::

Acyclovir, 800 mg orally twice a day.55 a day.53

Viral and Rickettsial Diseases

Valacyclovir, 500 mg orally twice a Acyclovir 800

day.56,57,58,59 mg orally twice
Valacyclovir, 1,000 mg orally once a a day.53 Acyclovir
day.58 800 mg three
Valacyclovir, 1,000 mg orally twice a times a day for 2
day.60,61,c days.53
Famciclovir, 500,c 250, 125 mg orally
twice a day.44,6263
Famciclovir, 1,000 mg orally twice a day
for 1 day (patient initiated).57,59,64
Famciclovir, 500 mg, then 250 mg twice
daily for 2 days.63
Suppression of Acyclovir, 400 mg orally twice a day.65 For children 12 Duration of the
recurrences Acyclovir, 800 mg orally once a day.66 years of age: therapy is con-
Valacyclovir, 500, 1,000 orally once a acyclovir, 400 troversial. Some
day.67,68,d mg orally twice a authorities will
Valacyclovir, 250 mg orally twice a day.53 offer treatment
day.65,d for 1 year and
Valacyclovir, 500 mg twice a day or then reassess the
1,000 mg orally once a day.60,61,69,70,c; need to resume
Famciclovir, 250 orally twice a day.71,72,73 it.
Famciclovir, 125 mg, 250 mg orally
three times a day.74
Suppression Acyclovir, 400 mg orally three times a
of recurrences day from 36 weeks of gestation until
in pregnant delivery.75,76
women Valacyclovir 500 mg twice a day from 36
weeks of gestation until delivery.77,78
Reduction of Valacyclovir, 500 mg orally once a day.11 Safer sex prac-
transmission tices should
continue to be
used.
a
The doses are for patients with normal renal function.
b
Oral dosage of acyclovir in children should not exceed 80 mg/kg/day. Children 40 kg and above should receive the adult dose.
c
Human immunodeficiency virus patients.
d
The high once-a-day and twice-daily doses of valacyclovir are more effective in patients who present with more than 10 recurrences per year.
Note: Neither valacyclovir nor famciclovir is approved by the US Food and Drug Administration for use in children.

2378
Box 193-4 Recommended Regimens for the Treatment of Ocular and Other
31
Cutaneous Herpes Simplex Infections
Acceptable Regimen Alternativesa

Disease Adults Pediatricb Duration Comments

Ocular Therapy 1% trifluridine drop1 Undertake in consulta-
herpes drop q2h during day (maxi- tion with an ophthal-
mum, 9 drops/day). until mologist. The combi-
corneal ulcer has healed, nation of interferon
followed by 1 drop every 4 and an antiviral may
h while awake (minimum 5 speed healing.80
drops/day) for an additional
7 days (to not exceed 21

Chapter 193
days)
3% vidarabine ointment
q3h during day (five times
daily); after reepithelializa-
tion, treat for an additional

::
7 days at a reduced dose

Herpes Simplex
(such as twice daily)
Acyclovir 3% ophthalmic
ointment five times daily for
710 days
Ganciclovir ophthalmic gel
0.15% 1 drop into affected
eye five times daily until
healed; then 1 drop three
times daily for 7 days
Acyclovir, 400 mg orally five
times a day.
Valacyclovir, 1,000 mg orally
two times a day.79
Suppres- Acyclovir, 400 mg orally For children Undertake in consulta-
sion of twice a day.81,82 12 years of tion with an ophthal-
recurrences Valacyclovir 500 mg daily81 age: acyclovir, mologist.
400 mg orally
twice a day.53
Other Treatment Acyclovir, 200 mg orally five Acyclovir, 710 days or No studies have been
cutaneous times per day. 480 mg/kg/ until resolu- done. Regimens are
herpes Acyclovir, 400 mg orally day orally tion of symp- extrapolated from the
(herpes three times a day. divided into toms. treatment of genital
gladi- Valacyclovir, 1,000 mg orally three to four herpes. Consider sup-
atorum, twice a day. doses pressive antiviral ther-
herpetic Famciclovir, 250 mg orally (maximum apy for patients with
whitlow, three times a day. 1 g/day)53 frequent recurrences.
etc.)
a
The doses are for patients with normal renal function.
b
Oral dosage of acyclovir in children should not exceed 80 mg/kg/day. Children 40 kg and above should receive the adult dose.
c
Human immunodeficiency virus patients.
d
The high once-a-day and twice-daily doses of valacyclovir are more effective in patients who present with more than 10 recurrences per year.
Note: Neither valacyclovir nor famciclovir is approved by the U.S. Food and Drug Administration for use in children.

2379
31 Box 193-5 Recommended Regimens for the Treatment of Neonatal Herpes,
Disseminated Infection, Encephalitis and Eczema Herpeticum
Acceptable Regimen Alternativesa

Disease Adults Pediatricb Duration Comments

Neonatal IV acyclovir, 20 mg/kg 1421 days. The value of long-
herpes every 8 hours.83 term suppression
after initial treat-
ment is being evalu-
ated.
Dis- IV acyclovir, 1015 mg/ IV acyclovir, 10 mg/kg 1421 days.
seminated kg three times a day. three times daily.53
Section 31

infection
Encepha- IV acyclovir, 1015 mg/ IV acyclovir, 1520 mg/ 1421 days.
litis kg three times a day. kg three times daily.53
Eczema Acyclovir, 200 mg orally Acyclovir, 4080 mg/ 1421 days. No studies have
::

herpeticum five times a day. kg/ day orally divided been done. Use IV
Viral and Rickettsial Diseases

Acyclovir, 400 mg orally in three to four doses acyclovir in severely

three times a day. (maximum, 1.2 g/d). ill individuals. Con-
Valacyclovir, 1,000 mg IV acyclovir, 10 mg/kg sider suppressive
orally twice a day. three times daily.53 antiviral therapy
IV acyclovir, 1015 mg/ for patients with
kg three times a day. recurrences. Ocular
involvement should
be treated in con-
sultation with an
ophthalmologist.
a
The doses are for patients with normal renal function.
b
Oral dosage of acyclovir in children should not exceed 80 mg/kg/day. Children 40 kg and above should receive the adult dose.
Note: Neither valacyclovir nor famciclovir is approved by the U.S. Food and Drug Administration for use in children.

only modest benefits so far. The infections are inher-
ently briefer and less symptomatic than genital her-
pes. Treatment is only effective if used very early in
the disease, especially in the prodromal or erythema
lesion stages. Patients who wish treatment should
have the medication available and be vigilant for the
earliest signs and symptoms of recurrence. When
treatment is felt to be required, the therapy of choice is
penciclovir 1% cream every 2 hours while awake, for
4 days.41 Treatment should be initiated as early as pos-
sible. When initiated within 1 hour of first symptoms
of recurrence, penciclovir sped the healing of lesions
(4.8 days vs. 5.5 days) and decreased the duration of
pain (3.5 days vs. 4.1 days). This regimen is approved
by the FDA. Docosanol 10% cream is approved by the
FDA for over-the-counter treatment of herpes simplex
labialis. It is to be applied five times a day at the first
sign of recurrence of herpes simplex labialis. There
has been no direct comparison with topical penci-
clovir. Oral acyclovir, 400 mg five times a day for 5
days, affords marginal benefit if begun in the earliest
hour or two of the outbreak. Famciclovir, 500 mg three
times a day for 5 days, when started within 48 hours
2380 after experimental ultraviolet radiation, decreased
the median time of healing from 6 to 4 days43 but is
not useful for the more usual sporadic cases of her-
pes labialis. A 1-day regimen of valacyclovir (2 g twice
daily for 1 day) decreased the mean duration of cold
sore episodes by 1 day when compared with placebo,
if started in the prodrome period. Similarly, a single
dose of famciclovir reduced time of healing of herpes
labialis lesions by approximately 2 days compared
with placebo.46 Creams and ointments containing 5%
and 10% acyclovir are not beneficial in recurrent her-
pes labialis.
The use of suppressive acyclovir for herpes labia-
lis is controversial. In one small study, oral acyclovir,
400 mg twice a day, was effective in decreasing recur-
rences of herpes labialis.48 In another study, suppres-
sive therapy with valacyclovir was more effective than
episodic therapy with valacyclovir for herpes labialis.50
In studies with skiers (who have significant sun expo-
sures), acyclovir 400 mg twice a day, was shown to
reduce recurrences in one study,47 whereas acyclovir,
800 mg bid, failed to prevent recurrences in another
study.92 Both perioperative famciclovir (125 or 250 mg
orally twice daily given 12 days before to 5 days after
the procedure) and valacyclovir (500 mg twice daily
for 14 days, starting either a day before or the day
of the procedure) appeared to reduce the recurrence
of orofacial HSV in patients undergoing facial laser
resurfacing.93,94 Valacyclovir has also been shown to
suppress recurrences of herpes gladiatorum.95
Herpetic eye disease should always be treated in
consultation with an ophthalmologist. Options usu-
ally involve topical antivirals, including vidarabine,
trifluridine, acyclovir, or ganciclovir. Topical antivirals
are effective in shortening the duration of dendritic
and geographic keratitis, and are used to prevent cor-
neal epithelial disease in patients with blepharitis and
conjunctivitis, as well as patients on topical steroid
therapy for corneal stromal inflammation and iridocy-
clitis.80 Oral acyclovir is also effective for dendritic and
geographical epithelial keratitis. Suppressive antiviral
therapy reduces the rates of all types of recurrent ocular
HSV disease, and it is most important for patients with
a history of HSV stromal keratitis because it can pre-
vent additional episodes and potential loss of vision.81,82
ANTIVIRAL RESISTANCE
Virtually all clinically relevant drug resistance has been
seen in immunocompromised patients. The primary
mechanism of acyclovir resistance is selection of viral
mutants defective or deficient in TK expression. Most
mutants that are TK deficient are somewhat attenuated
for virulence in vivo.
The treatment of resistant HSV infection is compli-
cated. First, one must make the diagnosis. Very few
people who claim to be resistant to one of the anti-
viral drugs actually harbor resistant virus. There is a
common misconception that treatment prevents all
recurrences. One should suspect resistance only in
people who continue to have culture-proven outbreaks
of unaltered frequency and severity, especially if the
lesions do not heal by themselves. When resistance is
suspected, virus should be recovered and tested specif-
ically for sensitivity to acyclovir. These tests are expen-
sive but are available through commercial reference
laboratories. Second, the options for patients with true
resistance are few and far from ideal due to the lack of
alternatives that are safe and easy to administer. Fos-
carnet inhibits replication of all known herpesviruses
in vitro and does not require activation by TK or other
kinases, and therefore can be effective in the treat-
ment of acyclovir-resistant HSV. Foscarnet requires
intravenous therapy and can cause numerous adverse
reactions including nephrotoxicity, electrolyte distur-
bances, anemia, and seizures. Also, foscarnet-resistant
HSV strains have been described.
Cidofovir does not require the viral TK for its intra-
cellular phosphorylation to the active form. Cidofovir
has been tested in cases of acyclovir-resistant HSV and
topical cidofovir has been used with success to treat
progressive herpetic lesions.96 Intravenous cidofovir
is associated with considerable nephrotoxicity and
requires the coadministration of saline hydration and
probenecid. A few patients with acyclovir-resistant
genital herpes have responded to imiquimod 5%
cream.97 Imiquimod caused severe inflammation in
some patients with recurrent herpes labialis.98 Resiqui-
mod reduced the rate of new lesions in one study of
31
persons without drug-resistant virus,99 but had no
effect on genital herpes in another study.100 Long-term
suppressive acyclovir therapy reduced the rate of
drug-resistant HSV disease in hematopoietic stem cell
transplant recipients.101
PREVENTION
Strategies to prevent HSV infection have proved
inadequate. HSV infection can be prevented by total
abstinence, as indicated by very low seroprevalence
Chapter 193
rates in cloistered nuns. Condoms reduce rates of
transmission if used routinely.102,103 Male circumci-
sion reduced the rate of HSV-2 infection from 10%
in the control group to 7.8% in the circumcised
group.103 Other than these public health approaches,
most efforts involve antiviral therapy and vaccines
::
directed at genital herpes.
Herpes Simplex
ANTIVIRAL THERAPY
Acyclovir, famciclovir, and valacyclovir decrease
both symptomatic and subclinical shedding of HSV-
2, from about 8% of the days in the placebo group to
0.3%0.6% of the days in the treatment group, when
assessed by culture.67,74,88,104,105 Once daily valacyclovir
reduced shedding by PCR from 14% to 3% in patients
with newly diagnosed genital herpes.106 Valacyclovir
500 mg once daily was shown to be effective in reduc-
ing the transmission of HSV-2 between partners by
48%, and reduced clinical disease in the susceptible
partner by 75% in a randomized, placebo-controlled
trial involving immunocompetent, heterosexual
couples in stable relationships.11 This therapy can be
recommended for individuals concerned about trans-
mission to a partner, in conjunction with the use of
condoms. Regarding other groups (e.g., homosexual
couples, nonmonogamous individuals, immunocom-
promised, and persons with asymptomatic HSV-2
infection), it is uncertain if the use of antiviral therapy
(and which regimen) would be adequate to decrease
transmission.
Vaginal microbicides are also being studied, mostly
focusing on decreasing HIV transmission, but some of
the compounds also have anti-HSV activity and may
also affect HSV transmission.107
VACCINES
The best public health strategy to reduce infection and
morbidity associated with HSV infection is develop-
ment of effective vaccines. Unfortunately, no vaccine
has proved to protect adequately against acquisition of
HSV (prophylactic) or to reduce the number of recur-
rent episodes (therapeutic), although there are hopeful
developments in these directions.
Recombinant glycoprotein vaccines containing
immunogenic HSV proteins have been developed and 2381
31 tested by multiple pharmaceutical and biotechnologi-
cal companies. In a preliminary study, a recombinant
HSV-2 glycoprotein D vaccine with alum adjuvant
decreased the frequency of symptomatic outbreaks in
patients with genital herpes. A modified form of the
vaccine (with added glycoprotein B and a lipid emul-
sion adjuvant known as MF59) did not decrease the
number of recurrences in patients with genital her-
pes, but did decrease the duration and severity of a
subsequent study outbreak of genital herpes.108 Two
phase III studies of the effect of this vaccine (one in
monogamous seronegative partners of individuals
with genital herpes, and the other in seronegative
persons attending clinics for sexually transmitted dis-
eases) failed to prevent acquisition of genital herpes
Section 31
infection or disease.109 A recombinant gD2 vaccine that
uses monophosphoryl lipid-A as adjuvant was pro-
tective against HSV-2 genital disease (but had limited
protection against infection) in HSV-1 and HSV-2 sero-
negative women but not in males or HSV-1 seroposi-
::
tive females.110 A double-blind, randomized controlled
Viral and Rickettsial Diseases
study in HSV-1 and HSV-2 seronegative women found
that the vaccine was not effective in preventing genital
herpes disease.
A major theoretical limitation of recombinant HSV
vaccines is their inability to induce broad and protec-
tive cellular immune responses, and therefore geneti-
cally engineered live vaccines have been developed.
Replication-defective viruses are capable of only a
single round of replication, and therefore have no
pathogenic potential while potentially inducing the
full spectrum of immune responses. The use of rep-
lication-defective HSV mutants has been tested with
success as a candidate vaccine in animal models. A
glycoprotein H-deficient virus had no effect on reduc-
ing HSV reactivation and clinical disease among
individuals with recurrent genital HSV-2 infection.111
Another replication-defective mutant, defective in
ICP8 (a single-stranded DNA binding protein) and
part of the helicase/primase complex, has demon-
strated to be immunogenic and protective in animals
but has not been tested in humans yet. DNA vaccines
for HSV have also shown promising results in ani-
2382
mal models, but resulted in very limited induction of
HSV-specific cellular immune responses in a phase I
human study.112
ACKNOWLEDGMENT
This chapter is dedicated to the memory of Stephen
E. Straus, a coauthor of this chapter in the seventh
edition.
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