Bioscientia Medicina: Journal of Biomedicine & Translational Research
eISSN (Online): 2598-0580
Genital Herpes in Human Immunodeficiency Virus Infected Patients
Stella Sunur1*, Izazi Hari Purwoko 1, Yulia Farida Yahya 1, Raden Pamudji1
1
Department of Dermatology and Venereology, Faculty of Medicine, Universitas Sriwijaya/ Dr. Mohammad Hoesin Palembang,
Indonesia
A R T I C L E
Keywords:
genital herpes
IN F O
A B S T R A C T
Genital herpes is a recurrent, lifelong sexual transmitted infection caused
Human immunodeficiency virus
HIV
by HSV, especially type 2. Genital herpes is the most common infection in
HIV patient. HSV-2 can increase the risk of HIV acquisition 2 to 3 times.
HSV-2
Clinical manifestations of genital herpes can be different between HIV *Corresp ondi ng author:
infected and non-HIV patients. HIV-infected patients have a high risk of
developing chronic and severe genital ulcers with atypical manifestation,
Stella Sunur
prolonged healing, and resistant to treatment, depends on CD4 count.
E-mail address:
Genital herpes can be diagnosed based on history, clinical manifestation,
stella.sunur@gmail.com
All
authors
have
approved the final
manuscript.
reviewed
an d
version of th e
laboratory and histopathologic examination. Management of genital herpes
includes education and counseling patients and sexual partners, systemic
antiviral, and symptomatic treatment.
https://doi.org/10.32539/bsm.v5i8.342
Introduction
Virus (HIV).2 The incidence of genital herpes cannot be
Genital herpes is a sexually transmitted infection
reported with certainty, but an estimated 500,000 new
caused by Herpes Simplex Virus (HSV), recurrent and
cases occur each year. According to the World Health
lifelong.1 There are 2 types of HSV, HSV-1 and HSV-2.
Organization (WHO), an estimated 491 million people
Generally, HSV-1 causes the majority of cases of
aged 15-49 years (13%) worldwide were infected with
orolabial herpes, while HSV-2 is associated with most
HSV-2 in 2016 and it tends to increase. The highest
cases of genital herpes. However, both can infect the
prevalence occurred in Africa (44% women and 25%
oral and genital areas.2,3 Herpes simplex virus type 2
men), followed by America (24% women and 12% men).
(HSV-2) is the most common cause of genital ulcers.
Prevalence also increases with age, with a peak of
The clinical manifestations of genital herpes can be
young adults and more women than men with an
seen clearly, but most infections are asymptomatic and
estimated 313 million women and 178 million men. 5,6
can be transmitted through sexual intercourse and
vertical from mother to fetus. 2,4
Typical lesions of genital herpes are grouped
vesicles with an erythematous base, pustules, and
Genital herpes is a common sexually transmitted
ulcers, accompanied by complaints of pain, itching,
infection worldwide and a risk factor for the acquisition
dysuria, vaginal / urethral discharge, and painful
and transmission of the Human Immunodeficiency
inguinal lymphadenopathy. There may be prodrome
758
symptoms such as fever, headache, malaise and
transmission is highest when there are lesions or
myalgia. The lesions heal within 2-3 weeks. Predilection
prodrome
in men in the glands of the penis and preputium,
asymptomatic viral shedding. Fifty to 90% of sexual
whereas in women on the vulva, perineum, buttocks,
partners are unaware that they are infected with HSV.
vagina, and cervix. The clinical manifestations of
Asymptomatic viral shedding occurs most frequently in
genital herpes can be divided into first episodes
the first year after the primary episode. 9
(primary and non-primary) and recurrent episodes. 1,2
symptoms,
it
can
also occur
during
HSV infection occurs when viral particles enter the
Human Immunodeficiency Virus (HIV) is the cause
skin or mucous membranes through abrasion or
of Acquired Immune Deficiency Syndrome (AIDS),
microtrauma. The entry of the virus is preceded by the
which is a syndrome with symptoms of opportunistic
attachment of the virus to the cell surface receptors
infections or certain cancers due to a decreased
(heparan sulfate). This fusion results in the viral capsid
immune system due to HIV infection.7,8 HSV-2
being transported to the nuclear pore and releasing
infection is the most common infection in HIV patients,
viral DNA
accounting for 60-90% of HIV-infected patients. HSV-2
transactivator of transcription, VP16, residing in the
infection increases the risk of HIV acquisition 2 to 3
tegument, initiates transcription of a 3 gene cascade.
times.5,6,8 The clinical manifestations of genital
Viral α gene (immediate-early) starts replication and
herpes patients with or without HIV can be different.
activates β gene (delayed-early). Genes β produce
Patients with HIV have a high risk of developing chronic
enzymes needed for viral replication such as thymidine
and severe genital ulcers with atypical features,
kinase HSV and DNA polymerase. The last γ gene
prolonged
expressed
healing,
and
are
easily resistant to
treatment. This depends on the CD4
codes
cells, wherein the
for
structural
prepackaged
proteins.
The
nucleocapsid formation of the herpes virus begins in
count. 4,9,10
the nucleus. The nucleocapsid together with the
Pathogenesis
Herpes
into
simplex virus-2 is a
double-stranded
envelope develops through the inner lamellae of the
the
plasma membrane. Envelope particles are transported
α-herpesvirus, is
to the cytoplasm through the plasma membrane by
neurotropic, rapidly replicates, and infects various cell
membrane-bound vesicles and the Golgi apparatus.
types such as epithelial cells, fibroblasts, neurons, and
The release of virion progeny takes place in the plasma
leukocytes.3,9,11 Herpes virus consists of 4 parts,
membrane. 9 Then the virus will spread to surrounding
namely the electron-opaque nucleus, the icosahedral
cells and damage epithelial cells to form vesicles
capsid around the nucleus, the amorphous tegument
containing cellular debris, inflammatory cells, and
containing viral encoded proteins around the capsid,
virion progeny. Next, the virus enters the sensory nerve
and the outer envelope with glycoprotein spikes on its
fibers and migrates to the sacral nerve ganglion. In the
surface. The capsid is a protein structure surrounded
ganglion of the sacral nerves, the virus causes latent
by a tightly attached, tegumentary membrane. The
infection where DNA transcription continues but at low
capsid and tegument are surrounded by envelopes
levels. These latent infections are lifelong which can
containing
and
undergo periodic reactivation and replication. When
polyamines. Glycoproteins function as an intermediary
reactivation occurs, the virus descends from the nerve
for the attachment of viruses to host cells and induce a
ganglion
deoxyribonucleic
acid
(dsDNA)
Herpesviridae family subfamily
glycoproteins
virus
(gB-gN),
from
lipids,
host immune response against viruses. 3,9
The incubation period for HSV ranged from 2-12
days (mean 4 days).12 Transmission of HSV infection
occurs through sexual contact with fluids from an HSV
infected patient such as semen, saliva or direct contact
with the vesicle fluid of herpes lesions.3 The risk of HSV
to
the
skin
or
genital mucosa.
This
reactivation process generally causes genital ulcers,
but it can also be asymptomatic. Herpes simplex virus
can also spread via lymph vessels to regional lymph
nodes.13,14 When an infection occurs, the body will
activate cellular and humoral immunity to control the
spread of infection and HSV replication. CD4 and CD8
759
lymphocyte T cells, natural killer cells (NK cells),
results in
undiagnosed genital herpes
and the
macrophages, and inflammatory cytokines such as
continuous spread of HSV-2 and HIV.15 There are 3
interferons-γ are important protective cells against
important mechanisms of HIV transmission in HSV-2
HSV. The cellular immune response is an important
patients, namely: 12
factor in determining the severity and recurrence of
1. Symptomatic HSV-2 genital ulcers cause local
HSV. The humoral immune response does not prevent
inflammation and damage to the genital tract
recurrences.
mucosa thereby facilitating HIV-1 entry during
9
It has long been known that there is a synergistic
relationship between HIV and HSV-2. HIV infection has
clinical
implications
and
can
lead
to
HSV-2
reactivation. HSV-2 infection increases the risk of HIV
infection acquisition and transmission (Figure
1).15,16
exposure to HIV-infected genital fluids.
2. HSV-2 genital ulcers selectively increase local
recruitment of CD4 T cells that are targeted for
mucosal adhesion of HIV-1.
3. Viral replication in HSV-2 lesions.
The high rate of asymptomatic herpes virus shedding
Figure 1. Inter-relationships between HSV-2 and HIV infections. 16
Some literature describes the mechanism of HSV-2
infection in enhancing HIV
acquisition primarily
HSV-2 also had a higher number of CD4expressing
CD69
T-cells
and
DC-SIGN-
through CD4 cell recruitment and increasing the
expressing cervical dendritic cells higher in the
expression of important HIV receptors at the port of
cervicovaginal mucosa. There is also an influx of
entry.
dendritic cells and CD4 and CD8 T cells into
-
HSV-2 infection can increase the concentration
recurrent HSV-2 ulcers. These cells, which have
of cervical HIV target cells. HSV-2 infection is
the CCR5, CXCR4, and DC-SIGN receptors,
associated with a 10-fold increase in cervical
persist for several months, despite resolution of
CD4 T cells expressing CCR5, which is the main
the lesion.16 Langerhans cells prevent HIV
target of mucosal HIV infection. Women with
transmission through the C-type lectin, langerin,
760
which can degrade the virus thereby reducing
8, and monocyte chemotactic protein-1 by
transmission of HIV to T cells. Herpes simplex
epithelial cells. 16
virus-2 can decrease the expression of langerin
so that Langerhans cells are more susceptible to
The clinical manifestations of HSV are varied and
HIV infection. This makes it easier for HIV to
can cause psychological and psychosocial problems.
infect Langerhans cells and T cells. Several other
The severity of clinical manifestations and recurrences
studies have shown that keratinocytes infected
is influenced by viral and host factors. The clinical
with HSV-2 produce human β defensins and LL-
manifestations of herpes can be divided into first
37 protein which can increase the expression of
episodes and recurrent episodes. The first episode was
HIV receptors in Langerhans cells. The two
divided into primary, in patients without previous HSV-
things previously mentioned prove that HSV-2
1 or HSV-2 antibodies, and non-primary, in patients
not only inhibits Langerin function but also
with previous HSV-1 or HSV-2 antibodies. Most HSV
makes it easier for Langerhans cells to become
infections are asymptomatic. 9 Predilection in men in
infected with HIV. T cells, the main target of HIV
the glands of the penis and prepuce, whereas in women
infection, migrate to the genital skin and mucosa
under the influence of the chemokine CXCL-9.17
The biopsy results containing the inflammatory
infiltrate showed that local HIV replication was 3
to 5 times more than in areas without the
inflammatory infiltrate.16
-
Clinical manifestations
HSV-2
infection decreases mucosal
innate
immunity and induces a mucosal inflammatory
response. HSV-2 infection caused a significant
reduction in secretory leukoprotease inhibitor
(SLPI) gene
expression by human
cervical
epithelial cells, which persisted despite acyclovir
treatment.
This
suggests
that
the
virus
downregulates SLPI as a strategy to avoid the
immune system. The SLPI gene can inhibit HIV
infection. Decreased SLPI concentrations lead to
increased transcription factor
κB
(NF-κB)-
mediated proinflammatory pathways. Herpes
simplex virus-2 can also directly activate NF-κB
which induces HIV replication. During infection,
HSV-2 induces innate and adaptive immune
responses in the genital mucosa. Chemokine
induction causes recruitment of CD4 T cells and
dendritic cells, which are the target of HIV
infection.
The
proinflammatory
mediators
produced by epithelial cells and immune cells
facilitate HIV replication. Herpes simplex virus-2
induces HIV replication directly in HIV-1 long
terminal repeat or indirectly through stimulation
of the production of TNF-α, interleukin (IL) -6, IL-
on the vulva, perineum, buttocks, vagina, and cervix. 1,2
Primary first episode genital herpes
Primary genital herpes is characterized by local and
systemic symptoms that last a long time. The most
common local symptoms are pain, dysuria, urethral or
vaginal discharge, genital and sacral paresthesias,
accompanied by painful inguinal lymphadenopathy.
Lesions occur 3-14 days after infection. Systemic
symptoms occur early in the course of the disease, after
a mean incubation period of 6-8 days, peak 4 days after
disease onset and subside slowly in 3-4 days later. The
most common systemic symptoms are headache, fever,
myalgia, lethargy and photophobia. About 40% of men
and 70% of women experience systemic symptoms
during the primary episode. 1,9
Local symptoms of itching, erythema, and pain
generally occur within 1-2 days of preceding the lesion.
The first lesions appear as small, clustered, painful
vesicles or pustules above the erythematous base,
break easily and form ulcers within 2-4 days.
Widespread lesions can coalesce to form large ulcers.
Atypical features such as deep necrotic ulcers may
occur. New cluster lesions may appear at week 2. At
week 3, crusting begins and the process of reepithelialization begins. When the lesion is on the
mucosa, usually no crusting or scarring occurs. On
physical examination, there is an enlarged inguinal and
femoral lymphadenopathy that is painful, hard, and
does not fluctuate, which occurs at week 2 or 3 and
persists even after the lesions have healed. 9
761
About 88% of women with a first-episode genital
herpes can be misdiagnosed as recurrent vaginitis,
herpes infection have cervicitis. Urethral discharge and
urogenital tract infection, or candida infection in
dysuria occur in one-third of men. The urethra was
women and as folliculitis, condom allergy, or other
clear and mucoid. HSV pharyngitis can occur with
dermatoses in men. 9
orogenital sexual contact. The duration of time taken
Genital herpes in HIV patients
from lesion onset to resolution in women was longer
The clinical manifestations of HSV infection in HIV
(mean 20 days) than men (mean 16,5 days) and the
vary depending on the patient's immune status.17 All
duration of viral shedding (onset of lesions to viral
clinical
culture still positive in the lesion) was around 12 days. 9
immunocompetent patients can occur in HIV patients,
Non-primary first episode of genital herpes
especially during its early stages. However, as the
manifestations
of
HSV
infection
in
About 50% of first-episode HSV-2 genital ulcer
immune status decreases, the clinical manifestations
patients have HSV-1 antibodies. HSV neutralizing
are often atypical, wider, longer lesion duration,
antibodies inactivate extracellular viruses and interfere
painful, easily resistant to treatment, and often
with the spread of HSV infection. Non-primary first-
recurrent, especially when the CD4 count is <250 cells
episode patients had a lower frequency of systemic
/ mm3.9,18,19,20 HSV infection in HIV patients also has
symptoms, shorter pain duration, fewer lesions, and a
local and systemic symptoms that last longer and
shorter duration of healing than primary infections. 9
spread the virus longer (more than 30 days), while the
Recurrent genital herpes
recurrence ranges from 0-20 episodes per year. The
At least 90% of infected patients have recurrent
recurrence frequency increases when the CD4 count is
HSV-2 genital herpes and 88% of them have at least 1
<50 cells / mm3.17 Atypical features may include (1)
recurrence within the first 12 months of the episode.
hyperkeratotic
Recurrence can be triggered by emotional stress, UV
condyloma acuminata or carcinoma of the verosa in
radiation, concomitant infections, and menstruation.
advanced HIV patients (2) vegetative plaque, expanded,
Most genital herpes patients can predict recurrence
confluent with ulceration with yellow exudate (Figure
through local prodromal symptoms, such as a mild
2) (3) chronic and persistent ulcers that are very painful
tingling sensation that occurs about 48 hours before
and large in size (Figure 3), and (4) generalized papular
the lesion develops. The risk of viral shedding is high
eruptions
during prodrome symptoms, even when there are no
papulovesicles, erosions, and crusts. Lesions may
lesions.
progressively become
False
prodromes
(prodromal
symptoms
in
/
the
verucous
form
of
lesions
discrete
hemorrhagic
mimicking
papules
and
or
necrotic.
without genital lesions) may occur and are more
Generally, it occurs in patients with CD4 counts less
common in patients who have frequent recurrences.
than 100 cells / mm3.9,21 Perianal herpes is common
Recurrent genital herpes is the mildest form, with few
in patients who have sex with men (MSM) with HIV /
vesicles arising (about 3-5), in the glans penis or
AIDS. This form is characterized by pain, the lesions
prepuce of men and is usually unilateral. Systemic
can last weeks to months, and tends to be a persistent
symptoms experienced 5% of men and 12% of women.
chronic ulcer. 19.20 The risk of asymptomatic HSV
Women experience genital ulcer pain more often with a
shedding was 4 times higher in HIV patients than
longer duration than men. Peak viral shedding
without HIV. There is an inverse correlation between
occurred within 48 hours of lesion onset and lasted 4
CD4
days. The mean time from onset to crusting is about 5
correlation between plasma HIV ribonucleic acid (RNA)
days.
days.
and shedding.9 In men, the lesion is on the glans penis
Occasionally, only itching, erythema and edema are
or shaft of the penis, while in women it is on the vulva,
found
ulcers
perineum, buttocks, vagina, or cervix. Complaints are
(asymptomatic). In patients with recurrent genital
accompanied by pain, itching, dysuria, vaginal or
herpes can also be found atypical features. Genital
urethral
Re-epithelialization
without
vesicles,
occurs
in
crusting
6-10
or
count
and HSV-2 shedding and a
discharge,
and
pain
in
direct
inguinal
762
lymphadenopathy. Prodromal symptoms such as fever,
headache, malaise and myalgia are common. 2
Figure 2. Vegetative ulcers of genital herpes in HIV patients. 9
Figure 3. Large and chronic ulcers in genital herpes patients with HIV. 9
especially in HIV patients.12 The laboratory tests used
were direct HSV detection from the lesion and indirect
serologics (Tables 1-3). For acute lesions, take a
Diagnosis and work-up
Although the classic clinical manifestations of HSV
can be diagnosed with accuracy, they should still be
confirmed by
laboratory examination
or
biopsy,
specimen from vesicle fluid. For longer lesions, the
diagnostic yield is very low. In this case, the patient is
advised to return if new vesicles develop.22 For tissue
specimen collection, a biopsy is performed on the edge
763
of the ulcer.3
70-90%
Laboratory examination
decreasing in asymptomatic patients. Herpes
1.
Direct
diagnosis
of
HSV
from
clinical
protein
in
can
symptomatic
also be
patients
detected by
and
ELISA
examination using HSV-specific monoclonal or
specimens
polyclonal
1.1. Cytologic examination
This
examination
uses
a
Tzanck,
Papanicolaou, or Romanovsky smear. 22 The
Tzanck smear is an easy, practical, and fast
diagnostic test to detect HSV, but it is
antibodies.
Compared
to
viral
culture, ELISA sensitivity was ≥ 95% with
specificity
ranging
symptomatic
patients. 22
from
62-100%
in
1.3 Virus isolation and typing on cell culture
nonspecific because it cannot distinguish HSV-
The most widely used cells for HSV isolation
1, HSV-2, and varicella. This examination
are primary human diploid fibroblasts and cell
should be performed if the lesion forms
lines, such as MRC-5 cells (human fibroblasts),
vesicles. The swab is carried out from the base
Vero cells (monkey
of the vesicle. A positive result shows typical
(laryngeal squamous cell carcinoma), hamster
When mucocutaneous lesions develop, the
viral antigen of the lesion can be detected by
immunofluorescence
(IF),
immunoperoxidase (IP) staining, or enzymelinked immunosorbent assay (ELISA). Direct
immunofluorescence (IF) is a rapid diagnostic
test and can differentiate between types of
HSV. HSV-1 and HSV-2 antigens can be
detected by fluorescein-labeled type-specific
monoclonal antibodies. The disadvantages of
this examination are that the reagent is quite
requires
microscope),
and
is
cells
tube should be examined daily using a
1.2 Virus antigen detection
expensive,
Hep-2
kidneys, and rabbit kidney cells. The culture
multinuclear giant cells. 19,10
direct
kidney),
tools
less
(fluorescent
sensitive than
stereoscopic microscope to check for the
characteristics of the cytopathic effect of HSV,
which generally occurs 24-72 hours after
inoculation. Characteristics of the cytopathic
effect of HSV are elongated and scattered cell
changes to become large, round, refractile,
ballooning, numerous, and granular. There
may also be focal cell necrosis, syncytia and
multinucleated giant cells. This examination
has a low sensitivity for recurrent lesions (2550%) and dry ulcer or crusted lesions, whereas
in primary and vesicle-shaped lesions, the
sensitivity can up to 80-90% 19,22
molecular examinations, with a sensitivity of
Table 1. Recommended specimen collection for the diagnosis of genital herpes. 22
Collection site
Male skin or mucosal lesions
(including the perianal area)
Tools for sample collection
o Sterile needles
o Sterile cotton-tipped,
Dacron, or nylon-flocked
swab
o Microscope slides
Male urethra
o Sterile cotton-wool, Dacron,
or nylon-flocked swab
Collection method
o Unroof the vesicles with a
sterile needle
o Collect the contecnt of the
vesicles with a sterile swab
and:
- Apply to a microscope
slide (for
immunofluorescence) or
- Place on transport media
for viral culture or NAAT
o Clean the external urethral
ostium (OUE) with a swab
moistened in saline
o Pull the prepuce backwards
to avoid contaminating the
specimen
764
Female skin or mucosal lesions
(including the perianal area)
Female urethra
o Cotton swab and gauze
o Microscope slides
o Sterile gauze swab (to
remove excess discharge)
o Sterile cotton-wool, Dacron,
or nylon-flocked swab
Cervix
o Vaginal speculum
o Sterile gauze swab
o Sterile cotton-wool, Dacron,
or nylon-flocked swab
2. Virus detection and quantification using
o Put a sterile swab into the
OUE (to a depth of 0.5-2 cm)
and collect urethral
exudates
o Similarly as for male skin or
mucosal lesions
o Clean the vaginal introitus
using sterile gauze swab
o Insert a sterile swab into the
urethra (to a depth of 0.5
cm) to collect exudates
o Insert a vaginal speculum
moistened with warm saline
solution, and clean the
cervical canal opening with
a sterile gauze swab
o Insert a sterile cotton-wool
swab or Dacron swab into
the cervical canal (to a depth
of 2 cm deep) and collect the
material from lesions
asymptomatic HSV
shedding.22 This
method
of
examination is often used and has replaced viral
molecular techniques
Nucleic Acid Amplification Test (NAAT) / Polymerase
culture as the gold standard, because the procedure
Chain Reaction (PCR) is the most sensitive test for
and transport are easy and readily available, more
detecting HSV, 11-71% superior to viral culture. The
sensitive, and faster. However, the price of this
Nucleic Acid Amplification Test can also detect
inspection is still expensive. 19
Table 2. Direct laboratory methods for HSV diagnosis. 22
Method
Principle
Specimens
Sensitivity
Specificity
Advantage
Loss
Cytological
examination
Tzanck smear,
Papanicolaou (Pap),
or Romanovsky
stains
Low
Low
Inexpensive
o Fresh lesions
o Suboptimal
sensitivity and
specificity
Virus
antigen
detection
Detection of infected
cells by direct
immunofluorescence
o Skin or
mucosal
lesions
o Biopsy
o Conjunctival
or corneal
smears
o Smears tissue
section
o Smear from
base of vesicle
Moderate (genital
ulcers: 70-90%;
asymptomatic:
<40-50%)
High (>
95%)
o Inexpensive
o Rapid (<4
hours)
o Typing
possible
o Swab
o Smears from
lesions
o Smear or
vesicular fluid
of exudate
from base of
vesicle
Moderate (80%)
High (90%)
o Reagent
cost
o Rapid (<4
hours)
o Does not
require
specimen
integrity
o Typing
possible
o Fresh vesicles
o Suboptimal
sensitivity
o Timeconsuming
o Labour
intensive
o Not
standardized
o Fresh vesicles
o Suboptimal
sensitivity
Immunoperoxidase
staining
765
ELISA
Rapid test device
Viral
culture
HSV cell isolation
Molecular
biology
Detection of HSV
DNA and / or
quantity by NAAT,
such as PCR
o Swab
o Vesicular fluid
or exudate
from base of
vesicle
o Swab
o Vesicular fluid
or exudate
from base of
vesicle
o Swab
o Skin lesions
o Vesicular fluid
or exudate
from base of
vesicle
o Biopsy
o Mucosa
without lesions
o Conjunctival /
corneal smears
o Neonates
Hight (genital
ulcers:> 95%)
High (62100%)
Unknown
Unknown
Point-of-care
testing
Not yet evaluated
o Low to high
depending on
clinical
manifestations
o Vesicle fluid:>
90%
o Swab: 70-80%
o Mucosa
without
lesions: 30%
o Ulcers: 95%
High (~
100%)
o Swab
o Skin lesions
o Vesicular fluid
or exudate
from base of
vesicle
o Mucosa
without lesions
o Vitreous fluid
o Corticospinal
fluids
o Blood
Highest (98%)
High (~
100%)
o Simplicity
of sampling
o Classically,
“gold
standart”
method
o Currently,
“preferred”
test
o Virus
typing
o Resistance
phenotype
testing
o High
sensitivity
o Currently,
“preferred”
test
o Allows
virus
detection
and typing
in the same
test
o Rapid
o Results in
24-48
hours, can
be <3
hours
o Resistance
genotyping
o Method of
choice for
CSF
o Less sensitive
than PCR
o Sample storage
and transport
conditions
influence
sensitivity
o Labour
intensive
o Expensive
o Specialized
laboratories
o Results in 2-7
days
o Specialized
laboratories
o Not
standardized
o Expensive
Table 3. Virological and serologic approaches for the diagnosis of HSV-2
Direct HSV-2
HSV-1 specific IgG
HSV-2
detection
specific IgG
Initial
Positive
Positive or negative
Negative
assessment of
genital lesions
Positive
Positive or negative
Positive
o Fresh vesicles
o No viral typing
with or without lesions.22
Interpretation
o Acute HSV-2 infection
o HSV-2 specific serologic
reset in 15-30 days
o Recurrent HSV-2
infection with HSV-2
infection was acquired
at least 6 weeks ago
766
No lesions
Recurrent
genital lesions
Cannot be
applied
Negative
Negative
Cannot be
applied
Positive
Negative
Cannot be
applied
Positive
Positive
Positive
Positive or negative
Positive
Negative
Negative
Positive
3. Serologic examination is indicative of HSV
o Patients are at risk for
infection with HSV-1
and / or orolabial or
genital HSV-2 infection
o Patients are at risk for
infection with genital or
orolabial HSV-2
o Old HSV-1 and HSV-2
infections
o Recurrent HSV-2
infection
o Possible recurrent
HSV-2 infection
o Other genital ulcer
diseases need to be
considered
coalesce and form multinucleated giant cells. These
changes initially appear in the basal layer, then involve
diagnosis
This examination is recommended in patients with
the entire epidermis layer. There are 2 degenerative
recurrent genital herpes, atypical features, resolved
changes to form intraepidermal vesicles, namely
lesions, and negative HSV cultures. Serologic testing of
ballooning degeneration and reticular degeneration. In
HSV-2 in HIV patients is part of the initial HIV
ballooning degeneration, cells become swollen and loss
evaluation and helps identify asymptomatic HSV
of attachment to surrounding cells forms acantholysis.
infection.15 HSV-2 infection can be diagnosed by
This is characteristic of viral infection. Tzanck cells
detecting a specific type of IgG against glycoprotein G
appear homogeneous with eosinophilic cytoplasm.
HSV-2 with a sensitivity and specificity of more than
Occurs mainly at the base of the vesicle and vesicles
95% in HIV patients.23 IgG antibodies are generally
are formed intraepidermally. In reticular degeneration,
negative in primary genital herpes because IgG can
epidermal cells become progressively swollen so that
only be detected 2-12 weeks after symptom onset and
the cells become large and clear, then rupture and form
persists. The HSV IgM test can detect the initial
vesicles. Reticular degeneration is not characteristic of
infection of a patient whose IgG level is not detected.
viral vesicles or bullae and can be seen in other
IgM is positive during disease reactivation, but it is not
diseases
specific for virus type. Due to these limitations, this
Eosinophilic intranuclear inclusion bodies appear in
examination is
swollen cells. There
not
recommended as
a
routine
such
as
allergic
is
a
contact
dermatitis.
large neutrophil and
lymphocyte infiltrate. 9,19,24
examination.9
Old lesions show lichenoid infiltrates or histiocytes
Biopsy and histopathologic
Initial changes appear to be swollen epidermal
with granulomatous inflammation. Verucous HSV
nuclei and appear slate-gray with peripheral chromatin
infection is characterized by widespread viral infection
clumping,
image
of the epithelium involving the adnexes, including
accompanied by nucleus ballooning and cytoplasmic
necrosis of the sebaceous glands, hair follicles, and
vacuolization (Figure 4 and 5). As the cells and plasma
sweat glands. Generally, verucous HSV infection is
membrane are not intact, the infected keratinocytes
found in patients with CD4 counts <200 cells / mm3. 3
homogeneous
ground
glass
767
Figure 4. The histology of genital herpes shows ballooning degeneration, spongiosis and acanthosis.9
Figure 5. (a) HSV infection shows intraepidermal bullae (b) Appears of multinucleated giant cells with nuclear
molding and thickened chromatin margins. 3
Management
There is no drug that can eliminate HSV from the
body. The goals of the management of HSV-2 infection
asymptomatic viral shedding, and risk of sexual
transmission.
- Effectiveness of suppressive therapy in first-episode
are to relieve symptoms, stimulate reepithelialization,
genital
reduce HSV-2 transmission, prevent lesions and
symptomatic episodes.
recurrence.9,15
Non-pharmacology
Education
Counseling patients and sexual partners is an
important treatment. The goal of counseling is to assist
patients in treatment and prevent sexual and perinatal
transmission. Some topics that can be discussed when
counseling patients with HSV infection are: 18
- Course of disease with possible recurrent episodes,
herpes
patients
to
prevent
recurrent
- Episodic therapy to reduce the duration of recurrent
episodes.
- Provide information to sexual partners about genital
herpes and potential partners before having the first
sexual intercourse.
- Potential sexual transmission of HSV that can occur
during the asymptomatic period (asymptomatic
viral shedding is more common
with HSV-2
infection than HSV-1 and generally occurs within
the first 12 months after infection with HSV-2).
768
- Abstinence of sexual activity when prodromal
the mainstay of therapy with a dose of 5-10 mg / kg
body weight every 8 hours for 2-7 days or until the
lesions or symptoms develop.
- The effectiveness of using latex condoms on men
consistently and appropriately can reduce (not
lesions heal, followed by oral antiviral therapy for a
minimum total of 10 days of total therapy. 10,18
eliminate) the risk of transmission of genital herpes.
In HIV patients, anti-HSV-2 suppressive therapy
- Asymptomatic HSV infection.
can be considered. Several studies have shown that
- Risk of neonatal HSV infection.
acyclovir, valacyclovir, and famciclovir can lower
- Increased risk of
HIV
acquisition in
HSV-2
plasma and genital HIV RNA levels, but the mechanism
seropositive patients who are exposed to HIV
for this is unknown. 25 The standard suppressive dose
(suppressive antiviral therapy does not reduce the
of acyclovir is quite effective. The suppressive therapy
risk of HIV transmission)
recommended by the CDC 2015 (Table 5) is acyclovir
400-800 mg, orally, two to three times per day; or
Pharmacology
There is no therapy that can eliminate the virus
valaciclovir 500 mg, orally, twice per day; or famciclovir
guidelines
500 mg, orally, twice per day 18 for at least 6-12
developed an algorithm for the management of herpes
months.19 The risk of resistance increases with severity
in immunocompromised patients (Figure 6). Episodic
of immunodeficiency. If the genital herpes lesions are
or suppressive systemic antiviral therapy is effective in
persistent or recurrent in the patient on adequate
reducing the clinical manifestations of HSV in HIV
antiviral therapy, HSV resistance can be considered
patients. In patients with advanced HIV, it is necessary
and virus isolation is required for sensitivity testing and
to consider giving an antiviral dose 2 times the
a biopsy can be performed. In HIV patients who are
standard dose and if lesions persist on days 3-5, the
resistant to acyclovir or its derivatives can be given
dose may be increased. Based on the Centers for
intravenous foscarnet (vidarabine) 40-80 mg / kg body
Disease Control and Prevention (CDC) 2015 (Table 4),
weight every 8 hours until reaching clinical resolution
the antiviral doses given to HIV patients with episodic
or intravenous cidofovir 5 mg / kg body weight once
genital herpes infection, namely: acyclovir 400 mg,
every week for 2 weeks. 2
from
the
body.
The
2017
European
orally, given three times per day for 5-10 days; or
Topical can be given imiquimod or cidofovir 1%
valaciclovir 1000 mg, orally, twice per day for 5-10
applied once a day for 5 days. 3,18 Topical antiviral
days; or famciclovir 500 mg, orally, twice per day for 5-
therapy in genital herpes is not recommended because
10
days.18
Treatment should be given for a minimum of
10 days or until the lesion is
re-epithelialized. 10
In
severe and complicated cases, intravenous acyclovir is
it is less effective than systemic therapy. Potassium
permanganate compresses can be applied to ulcer
lesions to prevent secondary infection. 3
Table 4. Episodic genital herpes therapy in HIV according to the CDC 2015. 10
Drugs
Acyclovir
Valacyclovir
Famciclovir
Dosage and method of
administration
3 x 400 mg orally
2 x 1000 mg orally
2 x 500 mg orally
Duration
5-10 days or until the lesions heal
5-10 days or until the lesions heal
10 days or until the lesions heal
Table 5. Suppressive therapy for genital herpes in HIV according to the CDC 2015. 10
Drugs
Acyclovir
Valacyclovir
Famciclovir
Dosage
and
method
administration
2-3 x 400-800 mg orally
2 x 500 mg orally
2 x 500 mg orally
of
Duration
Minimum 6-12 months
Minimum 6-12 months
Minimum 6-12 months
769
Immunocompromised patients with active HSV lesions suspect acyclovir resistance because of failed therapy with standard
antiviral therapy or previous acyclovir resistance
Confirm by PCR examination or viral culture
If new lesions persist after 3-5 days, increase the dose of acyclovir to 800 mg orally five times per day, or
valaciclovir 1 gram orally twice per day, or famciclovir 750 mg orally twice per day. Viral culture for resistance
testing. This examination takes 5 days.
Topical:
Foscarnet cream 1%
or
Cidofovir gel 1%
Systemic:
Intravenous foscarnet 40 mg / kg body
weight every 8 hours
or
Intravenous infusion of cidofovir 5 mg / kg
with oral probenecid and adequate prehydration to reduce the risk of
nephrotoxicity. Effective in acyclovir and
foscarnet resistant patients. The initial dose is
5 mg / kg body weight per week, given by
infusion within 1 hour, for 2 weeks.
Systemic therapy can be continued until the
Alternative:
Topical trifluridine 8 hours until the lesion
resolves alone or in combination with
interferon-𝛼
or
Imiquimod cream 3 times per week
Figure 6. Algorithm for the management of herpes in immunocompromised patients. 10
Prevention
either prophylactic or therapeutic, that has been
Several efforts can be made to prevent HSV-2
approved. In experimental animals, vaccine-
transmission, including: 9
-
induced
Abstinence. All patients should be advised to
immunity
fails
to
prevent
viral
replication in the genital tract and the presence
avoid sexual contact at the time of prodrome,
of latent infection in the sensory ganglion
lesions, and for several days after recurrence.
remains a challenge. 9
-
Limit the number of sexual partners.
-
Avoid partners with a history of genital herpes.
-
Appropriate and consistent use of condoms is a
Genital herpes is a sexually transmitted infection
practical approach that is good enough to
caused by HSV, especially type-2, is recurrent and
minimize the risk of acquiring genital herpes.
lifelong. HSV-2 infection is the most common infection
However, this does not completely prevent the
in HIV patients and can increase the risk of HIV
transmission of genital herpes.
acquisition 2 to 3 times. The main mechanism that
Vaginal and rectal microbicides can inactivate
occurs is the presence of CD4 cell recruitment and
the virus at the port de entry, but this is still in
increased expression of important HIV receptors at the
the research stage.
port de entry. Genital herpes patients with HIV have a
-
Antiviral therapy.
high risk of developing chronic and severe genital
-
Vaccine.
ulcers with atypical features, prolonged healing, and
-
Vaccines
against
HSV
have
been
widely
developed, but until now there is no vaccine,
Summary
are easily resistant to treatment. The diagnosis can be
made
based
on
history, clinical manifestations,
770
laboratory examination, and histopathologic biopsy.
The
antiviral therapy, and symptomatic therapy.
management given was education, systemic
Sexually Transmitted Infections. 2nd ed. New
References
1.
Corey L, Wald A. Genital herpes. In: Holmes KK,
Sparling PF, Stamm WS, Piot P, Wasserheit JN,
10. Patel R, Kennedy OJ, Clarke E, Geretti A, Nilsen
Corey L, et al., Editors. Sexually Transmitted
A, Lautenschlager S, et al. 2017 European
Diseases. 4th
guidelines for the management of genital herpes.
ed.
New York:
McGraw-Hill
Int J STD AIDS. 2017; 0 (0): 1–14.
Companies Inc; 2008. p. 399–437.
2.
3.
Cohen JI. Herpes simplex. In: Kang S, Amagai M,
11. Pertel PE, Spear PG. Biology of herpesviruses. In:
Bruckner AL, Enk AH, Margolis DJ, McMichael
Holmes KK, Sparling PF, Stamm WS, Piot P,
AJ, et al., Editors. Fitzpatrick's Dermatology in
Wasserheit JN, Corey L, et al., Editors. Sexually
General Medicine. 9th ed. New York: McGraw-
transmitted diseases.
Hill Companies Inc; 2019. p. 3021–34.
McGraw-Hill Companies Inc; 2008. p. 381–97.
Su W, Berthelot C, Cockerell CJ. Viral infections
Manifestations
of
HIV
22.
Johnston C, Corey L. Current concepts for
sexually transmitted herpes viruses. In: Gross G,
genital
Tyring
herpes
simplex
virus
infection:
SK,
editors.
Sexually
Transmitted
diagnostics and pathogenesis of genital tract
Infections and Sexually Transmitted Diseases.
shedding. Clin Microbiol Rev. 2016; 29 (1): 149–
New York: Springer-Verlag Berlin Heidelberg;
61.
2011. p. 209–15.
World Health Organization. Herpes simplex
2020.
Available
from:
14. Gupta R, Warren T, Wald A. Genital herpes.
Lancet. 2007; 370: 2127–37.
15. Lingappa JR, Celum C. Clinical and therapeutic
sheets/detail/herpes-simplex-virus#hsv2
issues for herpes simplex virus-2 and HIV co-
WH organization. Herpes simplex virus: global
infection. Drugs. 2007; 67 (2): 155–74.
2016.
Available
from:
16. Thurman AR, Doncel GF. Herpes simplex virus
and HIV: Genital infection, synergy and novel
https://www.who.int/bulletin/volumes/98/5/
approaches to dual prevention. Int J STD AIDS.
19-237149/en/
2012; 23 (9): 613–9.
Wiraguna A, Duarsa NW. HIV infection and
17. Desai DV, Kulkarni SS. Herpes simpex virus: the
AIDS. In: Daili SF, Nilasari H, Makes WIB, Zubier
interplay between
F, Roman R, Pudjiati SR, editors. Sexually
Studahl M, Cinque P, Bergstrom T, editors. Viral
Transmitted
Immunol. 2018; 28 (10): 546–55.
Infections.
5th
ed.
Jakarta:
Publishing Agency of the Faculty of Medicine,
HSV,
host,
and
HIV-1.
18. Workowski KA, Bolan GA. Sexually transmitted
University of Indonesia; 2017. p. 188–220.
diseases
Munawwar A, Singh S.Human Herpesviruses as
Recommendations and Report. US; 2015. p. 27–
Copathogens of HIV Infection, Their Role in HIV
32.
Transmission, and Disease Progression. J Lab
Physicians. 2016; 8 (01): 5–18.
9.
clinical
13. Doerr H, Gurtler LG, Wittek M.Biology of
infection prevalence and incidence estimates,
8.
Epidemiology,
York:
simplex virus infection. UpToDate. 2016. p. 1–
Cutaneous
https://www.who.int/news-room/fact-
7.
Albrecht.
New
editors.
virus.
6.
A
ed.
manifestations, and diagnosis of genital herpes
11–37.
5.
12. Mary
4th
in HIV disease. In: Cockerell CJ, Calame A,
Disease. UK: Manson Publishing Ltd; 2012. p.
4.
Delhi: Elsevier; 2012. p. 335–59.
treatment
19. Lautenschlager S.
guideline.
Human
In:
herpes
MMWR
viruses.
Braun-Falco´s Dermatology. 2020; 1–24.
Patel R, Sundaram S, Kumar B. Genital herpes
20. Mindel A. Genital herpes. In: Gross G, KS,
simplex infection. In: Gupta S, Kumar B, editors.
editors. Sexually Transmitted Infections and
771
Sexually Transmitted Diseases. New
York:
Springer-Verlag Berlin Heidelberg; 2011. p. 217–
42.
21. Ndowa F, Cham F, Dludlu S. Genital ulcer
adenopathy syndrome. In: Gupta S, Kumar B,
editors. Sexually Transmitted Infections. 2nd ed.
New Delhi: Elsevier; 2012. p. 643–51.
22. Belec L. Herpes simplex virus (HSV) infections.
In: Unemo M, Ballard R, Ison C, Lewis D, Ndowa
F, Peeling R, editors. The laboratory diagnosis of
sexually
transmitted
infections,
including
human immunodeficiency virus. Switzerland:
World Health Organization; 2013. p. 93-106
change of.
23. Posavad CM, Wald A, Kuntz S, Huang ML, Selke
S, Krantz E, et al. Frequent reactivation of
herpes simplex virus among HIV-1-infected
patients treated with highly active antiretroviral
therapy. J Infect Dis. 2004; 190 (4): 693–6.
24. Xu X, Yun SJ, Erickson L, Chen L. Diseases
caused by viruses. In: Elder DE, editor. Lever's
Histopathology
Of
The
Skin.
11th
ed.
Philadelphia: Wolters Kluwer; 2015. p. 1690–
759.
25. Chun HM, Carpenter RJ, Macalino GE, Crumcianflone NF. The role of sexually transmitted
infections
in
HIV-1
progression:
A
comprehensive review of the literature. J Sex
Transm Dis. 2013; 1–15.
772