Members of the herpesvirus family
ds DNA enveloped viruses
Virion has 4 basic structures - the envelope, tegument,
nucleocapsid, and a DNA-containing core.
nucleocapsid 105nm in diameter, 162 capsomers
The DNA molecule has 150 kb pairs, the DNA molecule is
infectious if delivered into permissive cells
Up to 100 proteins may be coded for, the exact number being
unknown.
The structure of the genome of HSV is similar to other
herpesviruses, consisting of long and short segments which
may be orientated in either direction, giving a total of 4
isomers.
The genome of HSV-1 and HSV-2 share 50 - 70% homology
They share several cross reactive epitopes
HSV-2 virus particle. (Courtesy of Linda M. Stannard,
University of Cape Town)
PAGE of HSV reveals 50 different polypeptides most of them
representing separate antigens. HSV shares some of its antigens
with other herpesviruses, in particular VZV. This cross reaction
can cause problems in interpreting results from CFTs and other
tests. Originally, the classification of HSV into 2 subtypes was
based on serology. Type specific monoclonal antibodies are now
available for typing and it is now apparent that many isolates
lie in an intermediary position serologically between the HSV-1
and HSV-2 prototypes. There may be a continuous spectrum of
strains between the classical HSV-1 and HSV-2 serotypes.
Endonuclease restriction typing mapping of HSV DNA provide a
reliable method of typing the virus. It is particularly useful in
epidemiological studies where the itinerary of a particular virus
can be traced. (As in the case of serology, there appears to be a
continuous spectrum of virus strains from the archetypal HSV-1
and HSV-2. The virus can be grown in many different animal
species and on many types of cell cultures. The 2 serotypes
behave differently eg. HSV-1 is more neurovirulent for rodents.
In cell cultures, HSV-1 often produces rounding or ballooning of
cells, whereas HSV-2 often causes infected cells to fuse.
A. Primary Infection ;- Man is the only natural host to
HSV, the virus is spread by contact, the usual site for the
implantation is skin or mucous membrane. The intermediate and
basal undergo acantholysis leading to vesicle formation. In
mucous membranes, the roof of the vesicle is unsafe and soon
collapses to form a characteristic herpetic ulcer. During the
primary infection, HSV spreads locally and a short-lived viraemia
occurs, whereby the virus is disseminated in the body. In most
cases, the seedlings come to naught, unless spread to the brain
occurs. Most importantly is the spread of the virus to the
craniospinal ganglia.
B. Latency ;- HSV is able to escape the immune response
and persists indefinitely in a latent state in certain tissues.
Appropriate techniques reveal virus in 50% of normal human
trigeminal ganglia and, to a lesser extent, in cervical, sacral
and vagal ganglia. This is irrespective of the person's herpetic
history. The exact mechanism of latency of the virus is unknown,
it may either be ;-
(i) true latency - the virus is non-replicative and is
maintained within the cell either integration into the
cellular chromosome or in an episomal form.
(ii) virus persistence - this is best described as dynamic
latency, whereby there is a tightly controlled low grade
productive virus infection not leading to the lysis of the
cell.
C. Reactivation ;- It is well known that many triggers
can provoke a recurrence. These include;
The mechanism of reactivation is still uncertain, the source
of the virus is in the craniospinal ganglion responsible for the
innervation of the location of the recurrence. Several models of
reactivation are proposed which depends on the static and dynamic
latency theories.
D._Special_Topics
1. Immunocompromised patients ;- CMI is crucial in the
control of HSV infection. People with deficiencies in humoral
immunity have no problems in controlling HSV infection whereas
those with deficiencies in CMI do. 3 groups of immunocompromised
patients are particularly at risk from serious HSV infection ;-
a. Patients receiving cytotoxic drug therapy
b. Organ graft recipients
c. HIV carriers
Generally, in these patients, the infection can often be
controlled on the easing of the immunosuppressive therapy. HSV is
a common cause of severe morbidity in bone marrow graft
recipients, whereas it causes much fewer problems in renal
transplant recipients. AIDS carriers suffer greatly from HSV
disease.
2. Ocular Herpes ;- 2 forms of herpetic ulcers are
recognized. One form is infectious with active virus replication,
the other postinfectious and trophic being secondary to
mechanical damage. The gravest form of ocular herpetic disease
occur when the virus spreads to the anterior chamber. The
mechanism of pathogenesis is unknown but there appears to be an
intense immunological reaction.
3. Herpes encephalitis ;- In over a third of the cases
of HSV encephalitis, there is a previous of recurrent
mucocutaneous herpes. It is not certain whether the virus had
recently arrived in the brain from a state of latency in a
sensory ganglion or that the virus is already present in a latent
state in the brain.
4. Erythema multiforme ;- Erythema multiforme is
associated with many disparate conditions including HSV
infection. Typically, the rash develop 10 days after the
appearance of the herpetic lesion.
HSV is spread by contact, as the virus is shed in saliva,
tears, genital and other secretions, By far the most common form
of infection results from a kiss given to a child or adult from a
person shedding the virus. The risk of infection to a non-immune
individual in contact with contaminated secretions can be as high
as 80%. There are 3 types of herpetic episodes ;-
1. Primary episode - the incubation period ranges from 5 -
15 days. The infection may be subclinical.
2. Reactivation - this refers to the reawakening of latent
virus
3. Initial or first episode - this refers to infection (
clinically apparent or not ) on an anatomical site which has
never before been the site for endogenous or exogenous virus.
Auto-innoculation for one anatomical site to another is
common, especially by scratching. It was said that HSV-1 causes
infection above the belt and HSV-2 below the belt. In fact, 40%
of clinical isolates from genital sores are HSV-1, and 5% of
strains isolated from the facial area are HSV-2. This data is
complicated by oral sexual practices.
Primary Infection ;- Primary infection is usually
trivial or subclinical in most individuals. It is a disease
mainly of very young children ie. those below 5 years. There are
2 peaks of incidence, the first at 0 - 5 years and the second in
the late teens, when sexual activity commences. About 10% of the
population acquires HSV infection through the genital route and
the risk is concentrated in young adulthood. Primary infections
of all kinds are rare after age 30.
Recurrent Infection ;- Following primary infection, 45%
of orally infected individuals and 60% of patients with genital
herpes will experience recurrences. The actual frequency of
recurrences varies widely between individuals. The mean number of
episodes per year is about 1.6. The actual frequency decreases
with age, increases with socioeconomic status and is related to
race. Many individuals never experience any clinically apparent
reactivation although more than half would be intermittently
shedding virus in saliva, tears, semen or genital ( cervical,
urethral, prostatic ) secretions.
Ocular Herpes ;- The eye is the site of infection in 3%
of all primary infections and occurs in tender childhood or early
adulthood. An initial eye infection in an already immune
individual can take place at any time. The recurrence rate is 40%
and most affected individuals will suffer reactivation at least
once within 2 years of the primary episode. The incidence of
ocular herpes is 50,000 cases pre year in the UK.
Genital Herpes ;- Genital herpes is essentially a
sexually transmitted disease and is rare in children before
puberty. Thereafter the incidence increases rapidly and reaches a
peak in the early thirties. The first episode is usually a
primary infection but can be an exogenous infection in an already
immune individual. The incidence of genital herpes is similar to
ocular herpes, with 50,000 new cases in the UK per year. Overall,
primary genital herpes infection account for 3% of all primary
infections.
Neonatal Herpes ;- The incidence appear to vary between
different countries inexplicably. The US has an incidence of 1 in
4,000 live births with 70 deaths p.a., whereas the UK has an
incidence of 1 in 10,000 with 3 or 4 deaths per year. The baby
may be infected from a variety of sources. It may be infected by
oral or genital lesions from the mother, a herpetic whitlow in a
nurse, the father's eye etc. However, the greatest risk factor
appears to be genital herpes in the mother. The child may be
infected prenatally, perinatally, or postnatally. Transplacental
infection can occur but is very rare and occurs during the
viraemia following maternal primary infection. Premature
rupturing of the membranes is a well recognized risk factor.
Transmission during the birth passage is the greatest hazard,
especially in the presence of a florid primary infection in the
mother. Neonatal herpes remains a rare disease. This may be due
to the transfer of passive immunity from the mother which
unfortunately, is not always protective. In a recent study, women
with either a primary or initial genital infection had a 30-50%
chance of transmission to the fetus as compared to 3% chance for
those women with recurrent infection. With primary infection, the
quantity and duration of virus shedding is larger and longer.
CNS Herpes ;- The following are thought to be
manifestations of HSV disease in the CNS ;
1. Psychiatric disorder - this is conjectural at present
2. Meningitis - this appears to be a rare complication in the
UK
3. Mild diffuse encephalitis
4. Severe focal encephalitis
5. Herpes Simplex Encephalitis of the newborn
Herpes simplex encephalitis (HSE) has a prevalence of 0.1 -
0.4 per 100,000. There is an annual incidence of 50 - 100 cases
in the UK. The disease is equally distributed between the 2
sexes. HSE can occur following the primary disease or in an
already immune individual. The possibilities are that (i) it is
part of the primary episode (ii) reactivation of endogenous
latent virus (iii) infection by an exogenous virus in an already
latently infected individual.
Exogenous Reinfections ;- The primary episode normally
affects a particular localized anatomical site. Thereafter, the
same site is prone to recurrences caused by reactivation of the
original virus. More rarely, virus reactivation can occur at a
site remote from the area of primary implantation (the virus
having been seeded to the remote site as a consequence of
viraemia or direct implantation), the other possibility is that
the lesion at the remote site is caused by another strain of the
virus eg. persons already immune to HSV-1 are prone to
reinfection by HSV-2 or another strain of HSV-1.
HSV is involved in a variety of clinical manifestations which
includes ;-
1. Acute gingivostomatitis
2. Herpes Labialis (cold sore)
3. Ocular Herpes
4. Herpes Genitalis
5. Other forms of cutaneous herpes
6. Meningitis
7. Encephalitis
8. Neonatal herpes
1._Acute_gingivostomatitis
Acute gingivostomatitis is the commonest manifestation of
primary herpetic infection. The severity of the disease varies
from trivial cases to extensive ulceration of the mouth, tongue,
gums and fauces. The ulceration usually affect the hard palate
rather than the soft palate. The patient experiences pain and
bleeding of the gums. 1 - 8 mm ulcers with necrotic bases are
present. Neck glands are commonly enlarged accompanied by fever.
Other symptoms include sore throat, dysphagia. The mouth disease
can be associated with lesions elsewhere, such as primary
herpetic dermatitis, ocular and nasal herpes, herpetic whitlows
and even genital herpes. During the acute phase, a lymphocytosis
may be present with atypical lymphocytes which may mimic
infectious mononucleosis. Acute gingivostomatitis is a self
limiting disease which lasts around 13 days. The onset of
improvement is abrupt, with rapid resolution of symptoms.
An example of gingivostomatitis
2._Herpes_labialis
Herpes labialis (cold sore) is a recurrence of oral HSV. The
most frequent site is at the vermilion border of the lips but
sores can occur elsewhere eg. on the cheek, chin, upper lip,
nasal fold or inside the nose in the septum. Recurrent intra-oral
ulcers are rarely caused by HSV. Multiple sites are rarely
involved in recurrences. A prodrome of tingling, warmth or
itching at the site usually heralds the recurrence. About 12
hours later, redness appears followed by papules and then
vesicles. These vesicles then burst, weep, dry, scab and then
heal. The length of the cycle is variable (5-12 days mean = 7
days), but is usually constant in that particular individual.
3._Ocular_Herpes
HSV causes a broad spectrum of ocular disease, ranging from
mild superficial lesions involving the external eye, to severe
sight-threatening diseases of the inner eye.
a. Primary HSV keratitis ;- In this condition, the
patient complains of foreign body sensation, pain, photophobia
and lacrimation. In the early stages, small predendritic ulcers
are seen on the cornea, neck lymphadenopathy and mild
constitutional symptoms may be present. The disease may heal at
this stage or progress with the development of a large dendritic
ulcer which has a serpentine branching appearance. Corneal
sensation can be impaired. The disease normally lasts 3 weeks,
during which the ulcer heals. Larger ulcers may take a longer
time to resolve.
b. Recurrent HSV keratitis ;- This is a severe
ophthalmic problem. There are no forms;
(a) dendritic, which resembles the lesions seen during the
primary infection but are often smaller. They do not normally
cause much scaring but people subjected to frequent
recurrences may suffer a slow deterioration in visual acuity.
(b) stromal form, which is a severe protracted disease of
the eye and causes opacification of the cornea and may lead
to necrosis of corneal fibres and rupture of the cornea.
c. HSV conjunctivitis ;- Conjunctivitis, blepharitis,
and circumocular dermatitis are commonly present during an attack
of primary kerititis. The diagnosis is particularly difficult in
the absence of corneal ulceration.
d. Iridocyclitis, chorioretinitis and cataract ;- Mild
reflex iritis is frequently seen as a complication of HSV
kerititis. A more severe form of iridocyclitis may be seen with
stromal keratitis. Chorioretinitis and cataract are
manifestations of neonatal herpes and can lead to damage or
permanent loss of vision.
4._Herpes_Genitalis ;- Genital lesions
may be primary, recurrent or initial. Many sites can be involved
which includes the prepuce, penile shank, scrotum, anus, vulva,
vagina, cervix, urethra (meatus or inside), bladder, the skin of
the perineum/buttock/thigh, the sacral nerve roots, the meninges
or the cauda equina and the cord itself. The lesions of genital
herpes are particularly prone to secondary bacterial infection
eg. S.aureus, Streps, Trichomonas and Candida Albicans. Dysuria
is a common complaint in primary, recurrent and initial genital
herpes. In severe cases, there may be urinary retention. Local
sensory nerves may be involved leading to the development of a
radiculitis. A mild meningitis may be present. Recurrent lesions
in the perianal area tend to be more numerous and persists longer
than their oral HSV-1 counterparts. The mean healing time in
recurrent genital herpes is 15 days, compared to 7.5 in oral
disease.
5._Other_forms_of_cutaneous_herpes;-
Herpetic dermatitis is a normal complication of the primary
mucocutaneous infection. Large areas of the face, perineum and
thigh may be involved. Under normal circumstances, HSV does not
readily penetrate normal skin. Persons with puncture injuries on
their skin may be become infected with HSV and develops herpetic
whitlows, especially health personnel who constantly manipulate
in the oral cavity. (dentists, dental nurses, anaesthetists). HSV
may also be spread by contaminated needles, razors, or broken
glassware. Herpes gladiatorum is a rare condition seen in
wrestlers. All forms of cutaneous disease can recur.
In herpetic whitlows, the patient complains of pain and
tenderness at the site of implantation. A single vesicle
develops, but satellite vesicles soon appears and rapidly
coalesce into a single necrotic oozing "abscess".
Healing takes around 15 days. The normal resistance of the skin
to HSV infection may be compromised in various dermatoses. There
are 2 forms of Kaposi's varicelliform eruption, and since the
withdrawal of smallpox vaccine, the more common form is eczema
herpeticum which is seen in patients with atopic eczema. Eczema
herpeticum as a primary infection carries a small mortality. A
distinct type of cutaneous herpes is called "zosteriform
herpes simplex". This is a rare presentation of herpes
simplex where HSV lesions appear in a dermatomal distribution
similar to herpes zoster. The disease cannot be diagnosed without
laboratory help.
6._Disseminated_Herpes_Simplex ;-
Disseminated herpes is uncommon outside the neonatal period in
immunocompetent persons. Dissemination may occur where the
patient's defenses have already been breached, eg. children with
Kwashiokor, measles, congenital defects in CMI. Disseminated
herpes can complicate burns, pemphigus or eczema, it has also
been described in pregnancy. Profound iatrogenic
immunosuppression carries the most risk eg. those undergoing
chemotherapy for ALL, or after BM transplantation. Childen with
congenital disoders of the thymus are also likely to develop
unusually severe HSV infection. Large doses of steroids in the
management of asthma or rheumatoid arthritis have similar
effects. One form of dissemination leads to eczema herpiticum, a
condition which is usually limited to the skin but may spread to
the liver, spleen, lungs or rarely to the CNS. HSV hepatitis can
occur but confirmed cases are extremely rare.
7._Herpes_Simplex_Meningitis,_Encephalitis ;-
Herpes simplex meningitis is usually a mild aseptic meningitis
which is almost always a complication of primary genital
infection by both HSV-1 or HSV-2. HSV-2 though, is the more
common cause. The most frequently encountered form of Herpes
simplex encephalitis (HSE) is a severe focal destructive
encephalitis with a mortality of 70% and severe neurological
sequelae in survivors. HSE can also present as a diffuse disease
with a good prognosis. HSE can have a sudden or insidious onset.
The prodromal phase lasts 4 - 10 days during which the patient
experiences non-specific symptoms (fever, malaise etc.) as well
as headaches and personality changes. This may progress into a
CNS catastrophe with seizures, visual defects, paresis, speech
defects, behavioral changes, stupor and coma. CAT scan may reveal
low density abnormalities and a mass defect, the EEG is always
abnormal and characteristically reveals delta slow rhythms and
periodic discharges and the CSF usually has a lymphocytosis.
8._Neonatal_Herpes ;- Once thought to be
a disease with a profoundly grave prognosis, neonatal herpes is
now known to cover a wide spectrum of severity. Subclinical cases
are rare but do occur without mouth or skin lesions. Where
dissemination occurs, infection carries a grave prognosis.
Infection is particularly dangerous in premature infants. In
mature infants, infection 10 days or more after birth carries a
much improved prognosis. In 75% of the cases, the infection will
disseminate throughout the body to many organs, such as the
liver, adrenals and brain. The involvement of the brain carries a
particularly grave prognosis. In the remainder of cases, the
infection is confined to the skin, eye or mouth. However, even
when the infection is limited to the skin, there is a serious
risk of developmental abnormalities (chorioretinitis,
microcephaly, spasticity, deafness etc.). A third of all
survivors are severely crippled.
The first manifestations of disease usually appear within 10
days of delivery, occasionally the incubation period may be as
long as one month. Poor feeding, weight loss, loose stools and
respiratory distress are early symptoms together with
characteristic lesions on the skin, mouth or the eye.
Splenomegaly is usual and there may be jaundice with liver
failure. If the adrenals are involved, Waterhouse-Friderichsen
syndrome ensues. Septicaemia and neonatal herpes share many
clinical features. Involvement of the CNS is common, with
prominent chorioretinitis and convulsions. In more recent
studies, 43% of infected children have disease localized to the
skin, eye, and mouth and 56% had either disseminated infection or
infection of the CNS. The mortality in the presence of treatment
with acyclovir is 20%, overall 50% of children were found to
develop normally at 1 year of life.
1. Light Microscopy - cells from the base of the
lesion, or wiped from a mucous surface, or biopsy material, may
reveal intranuclear inclusions (Lipschutz inclusion bodies).
Infected cells may show ballooning and fusion.
2. Electron Microscopy - Electron microscopy is not a
sensitive tool for the detection of HSV, except in the case of
vesicle fluids which often contain 108 or more
particles per millilitre. However, like light microscopy,
electron microscopy cannot distinguish between the different
viruses.
3. Direct examination by antigen detection - cells from
specimens are treated in ice-cold acetone. FITC is generally used
for staining of fixed material. It is more sensitive and specific
than light and electron microscopy (90% sensitive, 90% specific),
but cannot match virus culture. In terms of cost and technical
expertise, it is very much more demanding.
Cytopathic effect of HSV in cell culture, note the
balooning of cells (Courtesy of Linda Stannard, University of
Cape Town, S.A.) and positive immunofluorescence test for HSV
antigen in epithelial cell (Virology Laboratory, Yale-New
Haven Hospital)
4. Detection of Viral Nucleic Acid - A number of PCR assays are
available for the rapid diagnosis of HSV infection.
5. Virus Culture - infectious HSV-1 and HSV-2 are
amongst the easiest viruses to cultivate. The fresher the lesion,
the better the chance for recovery, ulcers and mucous membranes
should be swabbed as vigorously as possible. Virus transport
medium should be used but this is not critical provided that
desiccation is avoided. Saliva, urine, CSF and biopsy material do
not need transport medium. Inoculation should be carried out as
soon as possible. A wide range of cell lines are available for
isolation. At least 2 cell lines should be chosen. A typical CPE
may appear from day 1 onwards. Other viruses can occasionally
mimic the CPE of HSV. Formal identification of the isolate can be
carried out by immunofluorescence, complement fixation,
neutralization or electron microscopy.
6. Serology - CFTs are commonly used, as are indirect
haemagglutination (IFT) assays which are more sensitive than
CFTs. Weak antigenic cross reaction with VZV may occasionally
cause problems in these tests. ELISAs and RIAs are becoming
available and may gradually replace CFTs and IFTs. Seroconversion
from a zero baseline is usually diagnostic of a primary
infection. In the case of recurrent infection, an immune response
from a non-zero baseline may be detected. For immune status
screen, sensitive tests such as ELISAs and RIAs should be used as
insensitive tests such as CFTs may fail to detect very low levels
of HSV specific antibodies which are present years after a
primary infection.
In contrast to many other viruses, HSV specific IgM had proved
to be unhelpful in the diagnosis of primary infection as HSV IgM
may be present in cases of reactivation as well as primary
infection. In certain circumstances, HSV IgM may be useful in the
case of neonates when the presence of HSV IgM is a highly
significant finding, as can be its detection in the CSF of a
patient with suspected encephalitis.
Herpes_simplex_encephalitis ;- The
diagnosis of HSE is difficult, therapy should be commenced as
soon as possible where there is suspicion of HSE on clinical
grounds before the results of laboratory tests are known. HSE
cannot be diagnosed reliably by virus isolation from the CSF or
by IF using CSF cells. HSE is diagnosed by the following
methods;-
(a) HSV antigen by FITC conjugated anti-HSV antibodies
from brain biopsy cells.
(b) Virus culture from brain biopsy cells
(c) The presence of HSV virions or Lipschutz inclusion bodies
in brain tissue by electron or light microscopy.
(d) The demonstration of intrathecal synthesis of HSV
antibody.
Brain biopsy provides the best avenue for diagnosis but is
rarely carried out nowadays with the advent of acyclovir. For
determination of intrathecal HSV Ab synthesis, the integrity of
the blood-brain barrier should be assessed to ensue that any HSV
Ab present in the CSF is not a result of transudation from the
serum across a compromised blood-brain barrier to the CSF, as is
the case during the early stages of acute necrotizing
encephalitis.
Steriods have little place in the management of HSV infections
as they tend to exacerbate the situation through their
immunosuppressive effect. Every effort should be made to reduce
the dosage of steroids where herpes simplex develops in a person
receiving high dosage steroids eg. eczema, rheumatoid arthritis,
graft surgery etc. Steroids are only indicated in cases of severe
stromal herpes or erythema multiforme where hypersensitivity is
an important part of the pathogenesis. The general management of
severe mucocutaneous HSV infections include supportive
procedures, analgesia and antibiotic treatment of secondary
bacterial or candida infections.
B._Antiviral_chemotherapy
At present, there are only a few indications of antiviral
chemotherapy, with the high cost of antiviral drugs being a main
consideration. Generally, antiviral chemotherapy is indicated
where the primary infection is especially severe, where there is
dissemination and when sight is threatened. Urgent treatment is
required in the face of a life-threatening HSV infection in the
eczematous or immunocompromised patient, in the neonate, in HSE,
and in patients with eczema herpeticum. It is not necessary to
treat HSV disease if it is not sufficiently severe to warrant
hospital admission. Exceptions to the rule include painful
herpetic whitlows and all forms of ocular herpes. Recurrent
disease other than ocular disease in normal individuals rarely
merits specific chemotherapy.
Specific anti-HSV drugs are more effective in the treatment of
primary infection and should be given within 3 days of the onset
of symptoms. They are rarely effective if given more than 5 days
after the onset of symptoms. With recurrent disease, treatment
must be initiated in the prodromal phase before the appearance of
symptoms or treatment will prove to be valueless. The following
are anti-HSV drugs currently used in the UK.
1. Acyclovir - This is the drug of choice for most
situations at present. Acyclovir require the presence of a
HSV-encoded thymidine kinase in order to be converted into its
active acyclovir triphosphate form. Acyclovir triphosphate is a
potent selective inhibitor of HSV DNA polymerase and causes
premature chain termination when it competes with guanine
triphosphate for incorporation into newly synthesized viral DNA.
Acyclovir is available in 4 formulations (in parentheses,
licensed uses in the UK):
1. i.v. (HSV infection in normal and immunocompromised
patients)
2. oral (treatment and long term suppression of mucocutaneous
herpes and prophylaxis of HSV in immunocompromised patients)
3. cream (HSV infection of the skin and mucous membranes)
4. ophthalmic ointment
Acyclovir has few mild side effects and is generally very safe
to use. After prolonged high doses, acyclovir can cause bone
marrow depression but this is not likely to be encountered in
normal clinical practice. Acyclovir resistant strains of HSV have
been reported. These resistant strains fall into 3 categories:
1. Naturally occuring thymidine kinase negative variants
2. Thymidine kinase resistant mutants (Tk-)
3. pol mutants with a DNA polymerase resistant to inhibition
by acyclovir triphosphate.
Only Tk- variants have emerged in nature following the
therapeutic use of acyclovir. However, both types of mutants are
associated with reduced pathogenicity. Forscarnet and cidofovir are
the drugs of choice for the treatment of acyclovir resistant HSV.
2. Famciclovir - famciclovir is the prodrug
of penciclovir which is the active form and a guanosine analog.
It has a very high bioavailabiity of 77%. It is converted into
penciclovir by a two step process. The first step occurs in the
gut and the second step in the liver. It has a long half life in
the gut. It has a higher affinity for HSV thymidine kinase than
acyclovir but a lower affinity for HSV DNA polymerase than
acyclovir. It acts as an inhibitor of viral DNA polymerase and
also as a chain terminator. It is used for the treatment of
primary and recurrent genital herpes, and for long term
suppression of recurrent genital herpes.
3. Valaciclovir - valiciclovir is the prodrug of
acyclovir but is much more readily absorbed by the gut than
acyclovir. It is used for the treatment of primary and
recurrent genital herpes, and for long term suppression of
recurrent genital herpes.
4. Idoxuridine and trifluorothymidine - idoxuridine is
highly toxic when given systemically and is now only used in the
eye. trifluorothymidine is an excellent drug in ophthalmic
practice but it does not have a product license and is only
available on a named patient basis in the UK.
5. Vidarabine (ara-A) - intravenous ara-A can be used
for the treatment of neonatal herpes and HSE. It is not available
as an oral preparation but can be used topically in the treatment
of ocular infections. Ara-A does not have a product license for
use in the UK for treatment of HSV infections.
Acyclovir has all but replaced ara-A for systemic therapy.
This shift is not necessarily soundly based as there is little
evidence that acyclovir is more effective than ara-A when used
systemically. However, there is no doubt that ara-A is a much
more toxic compound than acyclovir as it can cause bone marrow
depression and its use should be monitored by regular full blood
counts. Topical therapy for mucocutaneous herpes is probably of
minimal benefit outside ophthalmic practice. Idoxuridine and
acyclovir cream are available for the treatment of oral or
genital herpes but are of doubtful value.
Prophylactic_antiviral_chemotherapy
Prophylactic anti-HSV chemotherapy may be indicated in the
following situations ;-
1. Bone marrow graft recipients - BM graft recipients
become intensely immunodeficient and HSV is an important cause of
post- transplant morbidity and death. Generally, acyclovir is
given as maintenance prophylaxis for 6 to 9 months, beginning 3
days before transplantation.
2. Patients who suffer frequent recurrences of oral or
genital herpes - A daily dose of acyclovir 800mg (1000 mg
during immunosuppression) will have a favorable effect on
recurrences. The current cost is over £1000 per annum though.
The response is better for herpes genitalis than labialis
lesions.
Herpes_Simplex_Encephalitis
It is still unclear whether the prognosis of HSE is affected
to a great extent by specific chemotherapy. The outcome in HSE is
dependent to a great extent on the quality of the general medical
care. Patients die from this disease because of the unremitting
cerebral oedema and damage to critical neurological systems. The
cerebral oedema should be aggressively controlled by
dexamethasone, osmotherapy (urea, mannitol, or glycerol),
hyperventilation, elevation of the head of the bed and if
indicated, by surgical decompression. Acyclovir is now the drug
of choice for the treatment of HSE. With the best treatment, the
mortality of HSE can be reduced from 70% to 30%. Ideally, brain
biopsy should be performed before specific antiviral chemotherapy
is given but there is at present, a great reluctance to perform
brain biopsy.
Ocular_Herpes
The management of ocular herpes is a highly specialized
subject. In general, topical steroids must never be prescribed in
any condition of the eye which carries the slightest suspicion of
being ocular herpes. Surgical cleansing of the cornea
(debridement) makes a significant contribution to healing and
complements local antiviral chemotherapy. Secondary bacterial
infection should be treated by antibiotics. There is a wide
choice of anti- HSV preparations available and selection is
difficult and mostly reflects personal preferences. A liberal
amount of ointment should be used 5 to 6 times a day. Steroids
are harmful and are strongly contraindicated in many forms of
ocular herpes. When inadvertently used, dendritic and
conjunctival ulcers fail to heal and spread to form large corneal
ulcers which may perforate. The only situation when steroids are
indicated are in the treatment of ocular herpes of the internal
eye.
On the whole, preventive measures against HSV infection have
been disappointing. The virus is ubiquitous and little or nothing
can be done to prevent the transmission of infection in
environmental terms. HNIG has not been effective in the
prevention of HSV infections. Prophylactic chemotherapy may be
given to those suffering from frequent and severe recurrent
herpes but the cost factor must be taken into account. In
clinical trials, a -interferon eye
drops have proved effective for the prevention of recurrent
dendritic ulcers.
The only area where there has been some success is the
prevention of transmission of infection to newborn babies by the
use of caesarean section. The actual decision of whether to carry
out a caesarean section or not is very difficult as maternal
genital herpes is common whereas neonatal herpes is rare.
Furthermore, asymptomatic shedding of HSV is common. Generally,
caesarean sections are not carried out for cases of recurrent
herpes (except where florrid lesions are present and with the
mother’s informed consent) but for cases where there is
florid primary infection. The neonate should be closely monitored
and acyclovir should be given on the merest suspicion of genital
herpes. If the mother develops primary HSV infection during the
first or second trimester of pregnancy, antiviral therapy may be
considered. If the mother contracts primary herpes during weeks
30-34 of pregnancy, she may be treated by a acyclovir followed by
Casarean section or normal delivery. The mother with primary
genital herpes between week 34 and term should be delivered by
Caesarean section. A woman who presents with primary genital
herpes while in labour may be treated with IV acyclovir, although
it is uncertain whether this will reduce the rate of
transmission.
HSV_vaccines - Several
recombinant subunit vaccines are being evaluated at present.
There is evidence to suggest that such vaccines may be effective
in reducing the frequency and severity of recurrent disease in an
already immune individual, but their efficacy in preventing
primary infection is uncertain. Primary infection per se is not a
condition worth preventing except in immunosuppressed patients.
However, such vaccines may be useful in preventing or attenuating
recurrent disease.
