Journal of
Oral Pathology & Medicine
doi: 10.1111/j.1600-0714.2009.00802.x
REVIEW ARTICLE
Varicella zoster virus: review of its management
M. B. Mustafa1, P. G. Arduino2, S. R. Porter3
1
Oral Medicine Section, Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, University of Khartoum, Khartoum,
Sudan; 2Oral Medicine Section, Department of Clinical Physiopathology, University of Turin, Turin, Italy; 3Oral Medicine, UCL,
Eastman Dental Institute, London, UK
Varicella zoster virus (VZV) is one of eight herpes viruses
known to infect humans. Primary infection causes vari-
cella (chickenpox), after which virus becomes latent.
Years later, VZV reactivates and causes a wide range of
neurological diseases. The aim of the present report was
to critically examine the published literature to evaluate
advantages and limitations of therapy of VZV infection in
both immunocompetent and immunocompromised
patients. Aciclovir (ACV) has been the drug of choice
for many years for the treatment of VZV infections.
Recently, other antiviral agents have been developed to
overcome the low oral bioavailability of ACV, as well as
to provide a more flattering dosage regime. Chickenpox
is a benign self-limiting disease in the majority of cases
and usually no specific treatment is required. Treatment
of shingles is indicated to reduce the acute symptoms of
pain and malaise, to limit the spread and duration of the
skin lesions and to prevent the development of post-
herpetic neuralgia. Different classes of drugs have been
used for the treatment of post-herpetic neuralgia. The
first choice of any of these medications should be guided
by the patients medical health, the likely adverse effects
of the drug and the patients preference.
J Oral Pathol Med (2009) 38: 673688
Keywords: antiviral; oral; perioral; therapy; VZV
Introduction
Infection by varicella zoster virus (VZV) has a
worldwide distribution. The primary infection typically
gives rise to varicella (chickenpox) among previously
healthy children and tends to be inuenced by climate
and geographical factors. Following primary infection
the virus remains latent; afterwards, reactivation gives
Correspondence: Dr Mayson B Mustafa, Oral medicine Section,
Department of Oral & Maxillofacial Surgery, Faculty of Dentistry,
University of Khartoum, P.O Box 102, Khartoum, 11111, Sudan. Tel:
+249914103720, Fax: +249 183 745612, E-mail: maysonmustafa@
yahoo.com
Accepted for publication May 14, 2009
J Oral Pathol Med (2009) 38: 673688
2009 John Wiley & Sons A/S All rights reserved
interscience.wiley.com/journal/jop
rise to shingles and related disorders. By contrast,
secondary infection usually aects adults, has no
seasonal pattern and tends to be associated with other
factors such as age and immunosuppression (1).
Oral lesions in varicella occur frequently and the
prevalence of it correlates with the severity of the
disease. Reactivation of the virus in the trigeminal nerve
gives rise to herpes zoster (shingles), which is character-
ized by a painful prodromal rash in the oro-facial
region. After the rash resolves, shingles may be compli-
cated by pain or dysaesthesia, often termed post-
herpetic neuralgia (2).
The present review adds to the current knowledge of
VZV infection management. A MEDLINE review up to
June 2008 was undertaken and the computer search was
complemented by a hand search of all bibliographic
references. The objective of this review is to analyse
critically the literature to evaluate the advantages and
limitations of antiviral agents in the treatment of VZV
infections for immunocompetent and immunocompro-
mised patients.
Antiviral agents
Most of the antiviral agents used for the treatment of
VZV infections are nucleoside analogues that require
phosphorylation by a viral thymidine kinase (TK) (3).
The reference antiviral agent is aciclovir (ACV), which
has been the drug of choice for many years for the
treatment of VZV infections. Recently, other antiviral
agents have been developed to over come the low oral
bioavailability of ACV as well as to provide a more
favourable dosage regime (Table 1) (4, 5).
Antiviral drugs are generally safe and well tolerated
but, sometimes, they can be associated with side eects
such as nausea, diarrhoea, abdominal pain and head-
ache. Rare but reversible neurological reactions, such as
dizziness and confusion, have been reported in patients
with limited renal clearance who were given high doses
of ACV intravenously. The symptoms were directly
associated with the high plasma concentration of the
drug (6). Furthermore, exacerbation of the renal fail-
ure occurs when it is given to patients with renal
 VZV literature review
Mustafa et al.
674
Table 1 Antiviral agents used for the treatment of varicella zoster virus infections
Drug Mode of action
Aciclovir Aciclovir is phosphorelated by viral thymidine kinase to
(Zovirax) aciclovir monophsphate and then by cellular enzymes to
aciclovir diphosphate and triphosphate
Aciclovir triphosphate is a competitive inhibitor of viral
DNA synthesis and act as a chain terminator
Valaciclovir Similar action to aciclovir
(Valtrex)
Penciclovir Similar action to aciclovir
(Denavir)
Famciclovir Similar action to aciclovir
(Famvir)
Brivudin Targeted at the viral DNA polymerase, both drugs can act
(Zostex) and as competitive inhibitors after intracellular phosphorylation
Sorivudine to BVDU-5-triphosphate. They can also act as alternative
substrates and be incorporated into viral DNA, leading to
reduced integrity and functioning of viral DNA
Vidarabine Mode of action is unclear. May act by selective
incorporation of vidarabine monophosphate into viral
DNA causing a decrease in the rate of primer elongation
and chain termination
Foscarnet Foscarnet inhibits viral DNA synthesis independent of viral
(Foscavir) thymidine kinase. It acts as a pyrophosphate analogue that
interferes with the binding of the pyrophosphate to its
binding site of viral DNA polymerase during DNA
synthesis
BVDU, (E)-5-2-bromovinyl-2-deoxyuridine; VZV, Varicella zoster virus.
insuciency. Therefore, dosage modication of ACV is
required in patients with abnormal creatinine clearance
(7, 8).
Mutations at the level of the VZV TK are responsible
for the development of VZV resistance to antiviral
agents, which depend upon the viral TK for their
phosphorylation. Recently, several case reports have
appeared on the emergence of ACV resistant strains in
patients with human immunodeciency virus (HIV)
following long-term ACV therapy. Foscarnet may
circumvent infections caused by ACV resistant VZV
(9, 10).
Management of chickenpox
Chickenpox is a benign mild self-limiting disease in the
majority of cases and usually no specic therapy is
required. Supportive treatment with calamine lotion,
cleansing oatmeal baths (to prevent bacterial superin-
fection) and analgesics or antipyretics (to control fever
and pruritus) may be useful (4). Paracetamol is the
preferred antipyretic to be used in children with
chickenpox. The use of non-steroidal anti-inammatory
drugs was found to be associated with an increased risk
J Oral Pathol Med
Pharmacokinetics
Low oral bioavailability, only 1520% of the dose reaches
the plasma
Following oral uptake, 54% of valaciclovir is converted to
aciclovir by intestinal and hepatic rst metabolism, thus
increase the bioavailability of aciclovir by three to four
times
Penciclovir inhibitory concentrations for HSV and VZV
DNA are 100-fold higher than aciclovir. However,
penciclovir has longer intracellular half-life (720 h)
compared with aciclovir (1 h). Penciclovir is poorly
absorbed when given orally
Rapidly absorbed when given orally, reaches maximum
concentration in the blood in about 1520 min. First pass
metabolism in the liver results in rapid conversion of
famciclovir to penciclovir, with an oral bioavailability of
penciclovir of 77%
Famciclovir has oral bioavailability three to ve times that
of aciclovir
Brivudin and sorivudine have better bioavailability than
aciclovir. Both drugs are more potent inhibitors for VZV
replication than aciclovir in vitro
Brivudin is administrated in a more convenient does (once
daily) compared with other aciclovir (ve times a day) and
valaciclovir and famciclovir (three times a day).
Vidarabine has relatively low activity, rapid degeneration
rate and poor aqueous solubility, which require the infusion
of large amounts of liquid
Foscarnet is active against thymidine kinase decient VZV
strains, which tends to be resistant to aciclovir in immuno
compromised patients
of severe skin and soft tissue complications among
children with varicella (11, 12).
A number of clinical studies have been undertaken to
evaluate the benet of using ACV for the treatment of
chickenpox in dierent age groups (Table 2). These
studies concluded that ACV is eective in reducing the
severity and duration of chickenpox in healthy children,
adolescents and adults, reecting the inhibitory eect of
the drug upon the virus transport to the epithelial cells
as well as its replication in the skin. The time of ACV
administration during the clinical illness is important for
the drug to be eective. Among all age groups, clinical
benet is observed when ACV is given within 24 h
following the appearance of the skin lesions (1316).
The benet of using oral ACV in adolescents and
adults is more signicant than in children (15, 16). This
marked clinical eect is due to the fact that chickenpox
is associated with more extensive cutaneous lesions,
fever and malaise among adolescents and adults as
compared with younger individuals. Particularly in
healthy adolescents, chickenpox may be associated with
residual lesions that persist for years or months after
the infection. ACV therapy among this age group in a
placebo-controlled trial resulted in a marked reduction

Table 2 Studies for the use of aciclovir in immunocompetent patients with chickenpox
Total study
References Type of study population
(13) Randomized double-blind 105
placebo-controlled
(14) Randomized double-blind 815
placebo-controlled
(15) Randomized double-blind 68
placebo-controlled
(16) Randomized double-blind 148
placebo-controlled
in the development of such residual hypopigmented skin
lesions at 4 weeks, indicating its eect in reducing viral
spread and destruction of skin cells in the deeper layers
of the dermis (15).
A reduction of the skin lesions in adolescents and
adults following the use of ACV indicates a lowering in
VZV associated viraemia, which may subsequently
reduce the risk of a chickenpox-associated pneumonia
in this age group. Therefore, the risk of such a life
threatening complication in adults may be prevented by
early administration of antiviral therapy (8). Healthy
adults who develop chickenpox-associated pneumonia
should be hospitalized and treated with intravenous
ACV (17).
Antiviral therapy given to children and adolescents
does not interfere with the induction of eective
humoral and cell mediated immunity against VZV
(18). There was no signicant dierence in the
antibody titre between individuals treated with ACV
and those who were not (14, 15). In one study,
children treated with antivirals had a transient reduc-
tion in serum antibody titre to VZV than the placebo
recipients 4 weeks after the onset of illness, both
antibody titres were similar 1 year later (13). More-
over, ACV given during chickenpox does not increase
the susceptibility of shingles among treated patients
(8). Furthermore, the degree of viral spread to the
environment is not aected by therapy. A study
showed that VZV DNA was detected in 33100% of
throat sample swabs from children with chickenpox by
day 7 of the illness, even after the administration of
oral ACV (19). Therefore, based on these studies, the
use of ACV for the treatment of chickenpox in
healthy children is optional as the disease is generally
self-limiting and symptoms can be controlled and
reduced with supportive therapy (8).
VZV literature review
Mustafa et al.
675
Age
(years) Drug used Findings
516 Aciclovir 20 mg day four Aciclovir caused sooner onset of
times a day for 57 days healing
212 Aciclovir 20 mg day four Aciclovir was started within 24 h
times a day for 5 days of rash onset. It reduced the new
lesions formation, accelerated
healing, reduced pruritus and
resulted in lower rate of residual
lesions after 28 days
1318 Aciclovir 800 mg day four Aciclovir was started within 24 h
times a day for 5 days of rash onset. It reduced the new
lesions formation and the maximum
number of lesions, alleviate consti-
tutional illness and also reduced the
residual hypopigmented lesions
>17 Aciclovir 800 mg ve times Aciclovir therapy was started
a day for 7 days within 24 h of rash onset and
caused reduction on the
maximum number of lesions and
the duration and severity of
illness. Aciclovir given 2572 h
after rash onset had no clinical
eect
The American Academy of Paediatrics does not
recommend the routine use of ACV in healthy children
with chickenpox. Instead, they recommended that it
should be considered for treatment in children 12 years
or older, those with chronic cutaneous or pulmonary
disease, those being treated with short or intermittent
courses of corticosteroids or aerosol corticosteroids and
those receiving long-term salicylate therapy. The rec-
ommended dose is 20 mg kg (maximum single dose of
800 mg) administrated four times a day for 5 days (20).
To date, the use of other antiviral therapy such as
valaciclovir, famciclovir or penciclovir for the treatment
of chickenpox in healthy individuals has not been
evaluated in clinical trials and they are not licensed for
the treatment of chickenpox (8). Recently, sorivudine
has been investigated for the treatment of chickenpox in
healthy adults. In a placebo controlled trial, sorivudine
given p.o. in a dose of 10 or 40 mg once a day for 5 days,
shortened the mean time of cutaneous crusting and
cessation of new lesion formation. Unlike ACV, the
eectiveness of sorivudine was not aected by the
duration of the rash before the onset of the therapy (21).
Treatment for immunocompromised patients
Intravenous ACV is used for the treatment of chic-
kenpox in immunocompromised children and adults.
Rapid and eective inhibition of the virus is achieved
by its administration at a dose of 500 mg m2 day
every 8 h as a 1-h infusion (8). In a placebo controlled
trial, intravenous ACV given to children with malig-
nancy reduced the incidence of chickenpox-associated
pneumonia from 45% to none (22). The recommended
duration of ACV therapy is for 7 days or until no
new lesions have appeared for 48 h (8). In immuno-
compromised individuals, ACV can still be eective
even if it is started up to 72 h after the appearance of
J Oral Pathol Med
 VZV literature review
Mustafa et al.
676
the skin lesions because of the prolonged course of
illness in this high-risk group. However, the disease is
better controlled when the therapy is started within
24 h and before visceral dissemination has occurred
(8, 23). Relapse of the cutaneous rash can still occur
after the use of antiviral therapy for 7 days. Some
patients may develop new lesions within few days or
24 h after treatment has ceased, which necessitates the
use of a second course. Furthermore, relapsing fever
or new symptoms should raise the possibility of
secondary invasive bacterial infection which may need
antibiotic administration along with the antiviral
therapy (8).
Vidarabine has also proved to be eective in the
treatment of chickenpox among immunocompromised
individuals. In a double-blind placebo-controlled study,
patients who received vidarabine in a dose of
10 mg kg day had more rapid reduction in the forma-
tion of new lesions and fever than those who received
the placebo. Furthermore, the incidence of life threat-
ening complications was signicantly lower in the
former group than in the latter group (24). Although
no randomized trials have compared ACV with vidar-
abine, an analysis at a paediatric centre showed that of
the 16 children given ACV, none developed chickenpox
pneumonitis, while 29% of patients treated with vidar-
abine progressed to pneumonia (25).
The use of oral ACV, famciclovir or valaciclovir has
not been evaluated in the treatment of chickenpox in
immunocompromised children (8). Limited clinical trials
have investigated the use of other agents for the
treatment of chickenpox among high-risk individuals.
For example, interferon-a has been used in the treat-
ment of chickenpox in a group of children with cancer.
Intramuscular administration of interferon-a 0.4 to
3.5 105 IU kg day for 5 days signicantly reduced
the duration of lesion formation and visceral dissemi-
nation (26).
Treatment for maternal and neonatal chickenpox
Prophylaxis, as well as treatment, is mandatory if
chickenpox occurs during pregnancy. Pregnant women
who have signicant exposure to chickenpox dened
as living in the same household with a person with active
chickenpox or shingles or face-to-face contact with a
person with chickenpox or uncovered shingles for at
least 5 min and have no history of chickenpox,
seronegative or in situations that serological testing is
not readily available, should receive zoster immuno-
globulin (27, 28). Zoster immunoglobulin takes some
time to be absorbed from the injection site to achieve an
immunoprotective level in the blood, therefore, it should
be given within 7296 h following chickenpox exposure
to prevent or modify the course of the disease (29, 30).
It has been recommended that oral ACV should be
considered as a prophylaxis for susceptible pregnant
women with signicant exposure who have not received
zoster immunoglobulin or who have any underlying risk
factors such as chronic lung disease or impaired
immunity (31). Intravenous ACV should be given when
severe chickenpox complications occur at any stage of
J Oral Pathol Med
pregnancy such as pneumonia, neurological symptoms
or haemorrhagic fever (27, 32).
Zoster immunoglobulin should also be given prophy-
lactically to an infant whose mother develops chicken-
pox up to 7 days before delivery or if the mother
develops chickenpox up to 28 days after delivery
because of the risk of severe neonatal infection. Infants
should be given zoster immunoglobulin as early as
possible after delivery or exposure and should be
carefully followed up as severe chickenpox may still
occur in about 50% of the infants despite receiving
passive immunization (3335). A recent study suggests
that the combination of intravenous immunoglobulin
given to high risk neonates soon after birth or postnatal
contact, and prophylactic ACV given intravenously
starting from 7 days after the onset of maternal rash
can eectively prevent the clinical perinatal chickenpox
(36). However, there is still a lack of sucient evidence
to support the use of this combination prophylactically
(31). Intravenous ACV should be administrated to
infants presenting with chickenpox and feeling unwell
whether or not they received immunoglobulin, and also
to immunocompromised infants who develop chicken-
pox, including premature babies (31, 37).
Management of shingles
Treatment of shingles is indicated to reduce the acute
symptoms of pain and malaise, to limit the spread and
duration of the skin lesions and to prevent the
development of post-herpetic neuralgia and ophthal-
mological complications in herpes zoster ophthalmicus
(38). The pharmacological approach for the treatment
of shingles is based on symptomatic relief and
antiviral therapy.
Symptomatic treatment
Symptomatic treatment of shingles depends upon the
patients condition, the stage of the rash, the severity of
pain and also upon patients response to antiviral
therapy. Skin lesions should be kept clean and dry to
reduce the risk of bacterial superinfection. Sterile, non-
occlusive, non-adherent dressings placed over the
involved dermatome will protect the lesion from contact
with clothing (39). Topical application of crushed
aspirin tablets dissolved in chloroform on the painful
skin surface was found to be eective in reducing the
pain during the acute phase (40). Pain relief can also be
achieved by the use of an appropriate non-opioid or
opioid analgesic that is often combined with neuroactive
agents such as amitriptyline (41).
Injections of local anaesthesia for selective sympa-
thetic nerve block have been widely used for symptom
relief during the acute stage of shingles. It is recom-
mended that in patients with severe acute pain that is
not controlled by any other means, sympathetic regional
or local anaesthetic nerve blocks may be used to provide
pain relief and possibly reduce the development of post-
herpetic neuralgia (42, 43). The ecacy of this treatment
approach is based on controlled trials and case series
studies in which nerve blocks administrated during the

course of the acute shingles provided eective, immedi-
ate and total pain relief (44, 45).
It has been hypothesized that decreased pain, inam-
mation and tissue damage during the acute phase of
shingles may reduce peripheral nerve sensitization and
central hyperactivity, which in turn lessen the likelihood
of having post-herpetic neuralgia (43); however, the
impact of using analgesics during the acute stage of
shingles upon reducing the incidence of post-herpetic
neuralgia is not known (41). This may be due to the lack
of adequate sample size, inappropriate follow up to
determine the duration of post-herpetic neuralgia, the
concomitant use of other therapies such as antiviral
agents as well as the non-standardized approach to
dene post-herpetic neuralgia (42). A retrospective study
showed that sympathetic nerve blocks terminated the
pain of acute shingles and prevented or relieved post-
herpetic neuralgia in more than 80% of patients treated
within 2 months of the onset of the acute phase of the
disease, after which time the success rate of this proce-
dure decreased signicantly (46). In a small-randomized
double blind placebo-controlled trial, the use of amitrip-
tyline during the acute phase of shingles was signicantly
associated with reduced incidence of post-herpetic neu-
ralgia among elderly people. However, the drug is poorly
tolerated by this age group (47). In another study, the use
of epidural local anaesthetic and steroid was proved to be
signicantly more eective in preventing post-herpetic
neuralgia at 12 months in comparison with intravenous
ACV and prednisolone (48).
Antiviral agents
Shingles is a self-limiting disease and complete healing
usually occurs when it aects the trunk or the extrem-
ities of young individuals without risk factors. Antiviral
therapy has the benet of shortening the healing process
and seems to be important when a complicated course of
the disease is expected (38). Urgent systemic antiviral
treatment is necessary in patients over 50 years of age, in
immunodecient patients, in those with cranial nerve
involvement (as in herpes zoster ophthalmicus or zoster
oticus) and in patients with vesicles involving more than
one segment. Systemic antiviral therapy must be initi-
ated as early as possible in the disease course, within
48 h to a maximum of 72 h after the onset of the skin
lesions. Later therapy may still be eective in special
situations such as disseminated shingles with evidence of
immunosuppression and involvement of inner organs
and in persisting herpes zoster ophthalmicus and zoster
oticus (38, 43).
To date, ACV, valaciclovir, famciclovir and, in
Europe, brivudin are the standard antiviral agents for
the treatment of shingles in immunocompetent patients.
There is no role for topical antiviral drugs in the
management of shingles (39).
Aciclovir
Aciclovir is widely used for the treatment of shingles
and, unlike other antiviral agents, is the only agent that
can be given enterally or parenterally. It was found to
reduce the number of days for new-lesion formation, the
VZV literature review
Mustafa et al.
677
extent of involvement of the primary dermatome and
the time of crusting and healing (49, 50). The drug is
particularly eective when used for the treatment of
herpes zoster ophthalmicus, as it reduces the incidence
and severity of ocular complications such as pseudo-
dendritic keratopathy, episcleritis, iritis and stromal
keratitis (51, 52). ACV was also found to be eective in
reducing the severity of zoster-associated acute phase
pain. A meta-analysis of all the placebo-controlled trials
of ACV treatment for shingles showed a signicant
reduction in zoster associated pain among treated
recipients (53). ACV is given in an oral dose of
800 mg, ve times a day for 7 days. This high and
frequent dose is necessary due to its poor oral bioavail-
ability (1520%), low anti-zoster virus activity and its
short half-life (7).
ACV has a limited and less predictable eect in
preventing the development of post-herpetic neuralgia
because of the conicting results from associated clinical
trials (50, 54). However, re-analysis of data from a
placebo-controlled treatment trial of 187 immunocom-
petent people with shingles demonstrated that pain
duration among ACV recipients was 20 days compared
with 62 days for their placebo counterparts, indicating
that ACV reduces zoster associated chronic pain (55).
Moreover, a meta-analysis of ve clinical trials found
that oral ACV, given in a dose of 800 mg day, within
72 h of the rash onset, may reduce the incidence of
residual pain at 6 months by 46% in immunocompetent
adults (56).
The use of ACV, in combination with corticosteroids
has been investigated in two clinical trials. In both
studies, combination of the two drugs resulted in
moderate but statistically signicant acceleration in the
rate of cutaneous healing and remission of acute pain
with improvement in the patients quality of life.
However, neither study demonstrated any eect of
corticosteroids on the incidence or the duration of
post-herpetic neuralgia (57, 58). The use of corticoster-
oids for shingles without concomitant antiviral therapy
is not recommended (39).
Valaciclovir
Valaciclovir is an eective and well-tolerated antiviral
agent for the treatment of shingles. Because of its better
bioavailability compared with ACV, it is recommended
orally in a more convenient, less frequent dose of
1000 mg, three times a day for 7 days, which results in
better patient compliance and low incidence of adverse
side eects (59). Valaciclovir has similar ecacy to ACV
on the resolution of the cutaneous lesions and on the
prevention of long-term ocular complications of herpes
zoster ophthalmicus (60, 61). More importantly, pa-
tients treated with valaciclovir have more satisfactory
outcome in pain control than those treated with ACV.
In comparative trials, valaciclovir was signicantly more
superior than ACV in shortening the duration of
herpes zoster-associated pain (60, 62) and in reducing
the prevalence of post-herpetic neuralgia as well as
the duration of abnormal sensations such as hyper-
sensitivity, numbness, and allodynia (60).
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 VZV literature review
Mustafa et al.
678
Famciclovir
Famciclovir is used for the treatment of shingles in
immunocompetent people in a dose of 500 mg orally
three times a day for 7 days (7). The ecacy of
famciclovir in the treatment of shingles was proved in
a large placebo-controlled double blind trial involving
419 immunocompetent adults who received famciclovir
in a dose of 500 or 750 mg three times a day for 7 days.
Famciclovir accelerated the rate of cutaneous lesion
healing and reduced the duration of viral shedding.
Most importantly, this study revealed its signicant
eect on the reduction in the duration of post-herpetic
neuralgia (63).
In comparison with ACV, when treatment was
commenced within 72 h following onset of rash, all
dose levels of famciclovir (250, 500 and 750 mg)
administered three times daily were found to be as
eective as ACV (800 mg) for cutaneous lesion healing
(as indicated by the time to full crusting), cessation of
new lesion formation, loss of vesicles, loss of crusts and
time to loss of acute pain (64, 65). However, time to
resolution of zoster-associated pain occurred at a
signicantly faster rate in patients treated with famci-
clovir within 48 h of rash onset compared with ACV
treatment (64). These two studies did not report the
impact of famciclovir on post-herpetic neuralgia in
comparison to ACV.
A recent study demonstrated that famciclovir is
eective in the treatment of shingles when given less
frequently than three times a day. Famciclovir admin-
istrated in doses of 750 mg once daily, 500 mg twice
daily or 250 mg three times daily is as eective as ACV
administrated ve times a day, in the cutaneous healing
and the reduction of the acute phase pain, thus
improving convenience for patients and provide greater
adherence to the therapy (66).
Famciclovir and valaciclovir were compared for the
treatment of shingles in immunocompetent patients. In a
randomized comparison study, famciclovir, in a dose of
500 mg three times a day, was therapeutically equivalent
to valaciclovir in speeding the resolution of zoster
associated pain, rash healing and post-herpetic neuralgia
(67).
Brivudin
Brivudin was rst available for the treatment of severe
shingles in immunocompromised people. Later it
became available in Germany and other European
countries (Austria, Belgium, Greece, Italy, Luxembourg,
Portugal and Spain) for the treatment of shingles in
immunocompetent individuals (68). Brivudin, given in a
single dose orally of 125 mg, was conrmed by many
clinical studies to be superior to other antiviral agents in
the treatment of shingles. In a double-blind randomized
study, brivudin 125 mg once daily for 7 days was found
to be superior to ACV 800 mg ve times daily in
terminating the vesicle formation and hence stopping
the viral replication in acute shingles (69). Furthermore,
treatment with brivudin 125 mg once daily for 7 days
during acute shingles in immunocompetent elderly
patients resulted in a signicantly lower incidence of
J Oral Pathol Med
post-herpetic neuralgia than the standard treatment of
ACV; however, the mean duration of the post-herpetic
neuralgia was similar in the two groups (70).
Comparing the ecacy of brivudin (125 mg, once a
day) and famciclovir (250 mg, three times a day), both
drugs given orally for 7 days for the treatment of
shingles, resulted in equivalent ecacy in being able to
accelerate the stop of vesicle formation and lesion
healing. They also demonstrated equivalent ecacy
regarding the prevention of post-herpetic neuralgia
(71).
Thus, the results of comparative studies of brivudin
vs. ACV and famciclovir showed the importance of
brivudin in respect to reduced total daily dose (125 mg)
and a reduced dosing frequency (once daily drug intake)
which provide a more convenient treatment for elderly
patients (68).
Treatment for immunocompromised patients
Several antiviral agents were found to be eective in the
treatment of shingles in immunocompromised patients
(Table 3). ACV is given intravenously in immunocom-
promised patients, who are at high risk for disseminated
disease, at a dose of 510 mg kg given every 8 h.
Treatment is continued for 7 or 2 days after the
cessation of new-lesion formation (72). However, recur-
rent episodes of shingles may still occur in some
immunocompromised patients within few days or weeks
after antiviral therapy has ceased but most patients
respond to a second course of ACV. These episodes are
usually attributed to the poor host response rather than
to the drug resistance. Oral ACV may be accepted for
the treatment of recurrent shingles in immunocompro-
mised patients who are at low risk for visceral dissem-
ination (73). Although shown superior ecacy in the
management of shingles, the use of valaciclovir in the
treatment of zoster among immunocompromised pa-
tients has not been fully evaluated. However, a recent
study shows that valaciclovir 1 and 2 g, three times a
day are safe and eective in cutaneous healing and
reducing pain among immunocompromised patients
with zoster (74).
In a randomized, double-blind, multicentre, ACV-
controlled study, oral famciclovir was found to be a
convenient, eective and well-tolerated regimen for
immunocompromised patients with herpes zoster (75).
Vidarabine is also used for the treatment of shingles
among high-risk groups. It is given in a dose of
10 mg kg day over 12 h for 7 days. Studies have
compared the ecacy of ACV and vidarabine in the
treatment of shingles in immunocompromised peoples.
The results showed that ACV may be equal or more
eective than vidarabine in accelerating the cutaneous
healing and preventing the dissemination of shingles in
immunocompromised patients (76, 77).
Brivudin and its counterpart sorivudine are the most
potent inhibitors for VZV replication in vitro that have
ever been described (68). As a result of this unique
potency, both agents have been investigated for the
treatment of shingles in immunocompromised patients
in limited clinical trials which proved their ecacy (78,

Table 3 Studies for the treatment of shingles in immunocompromised patients
Total study
References Type of study population
(73) Randomized - controlled 27
(74) Randomized double- 87
blind, controlled
(75) Randomized double- 148
blind - controlled
(76) Randomized - controlled 22
(77) Randomized double- 73
blind - controlled
(78) Randomized double-blind, 20
Placebo controlled
(79) Randomized double-blind, 170
comparative
(80) Randomized double- 48
blind, comparative
79). Recently, in a randomized double-blind trial,
brivudin given orally at 7.5 mg kg day (that is 125 mg
four tablets per day) proved to be as eective as ACV
given intravenously at 30 mg kg day in the treatment of
shingles in immunocompromised patients (80). More-
over, in another randomized double-blind clinical trials,
sorivudine given orally at 40 mg daily was compared
with ACV given orally at the standard dose of 800 mg
ve times a day. Both drugs were given over a 10-day
course to HIV patients with shingles. The sorivudine
treatment resulted in similar ecacy to ACV regarding
the time to the resolution of zoster-associated pain, the
frequency of dissemination and the frequency of zoster
recurrence. Moreover, sorivudine signicantly acceler-
ated cutaneous healing (79).
Although proven to be eective in the treatment of
shingles among immunocompromised patients, the use
of brivudin and sorivudine has not been licensed
worldwide. Serious interactions have been documented
in immunocompromised patients receiving sorivudine or
brivudin with intravenous 5-uorouracil (used for
treatment of solid tumours). Bromovinyluracil is a
metabolite of sorivudine, as well as brivudin, which acts
as an inhibitor of dihydropyrimidine dehydrogenase
(DPD) which is needed for the degeneration of uoro-
uracil. This protects the breakdown of uorouracil and
signicantly increases its half-life, hence enhancing its
antitumour activity and toxicity (68, 80). Marked
increase in 5-uorouracil half-life have been demon-
strated in cancer patients who had been given 5-
uorouracil intravenously, concomitantly with oral
brivudin (81). In addition, fteen deaths occurred in
1993 among Japanese patients following the co-admin-
istration of sorivudine with 5-uorouracil 40 days fol-
lowing the approval of sorivudine by the Japanese
government to be used clinically (68, 82). Sorivudine
was also found to produce a profound depression on
VZV literature review
Mustafa et al.
679
Drug used Findings
Oral vs. intravenous No dierence was found between 2 treated
aciclovir groups in the days of healing and persistence
of pain.
Valaciclovir 1 g and Both dosage were eective in reducing zoster
2 g dosage 3 times day associated pain and abnormal sensation.
Famciclovir vs. Aciclovir No dierence between the eect of both drugs
on new lesions formation, full crusting and
loss of pain.
Vidarabine vs. aciclovir Aciclovir was better than vidarabine in
(intravenous) accelerating healing and preventing
dissemination of the disease.
Aciclovir vs. vidarabine No dierence between the eect of both drugs
on vesicles healing and frequency of
post-herpetic neuralgia.
Brivudin Brivudin stopped the progression of the disease
within 1 day after initiation of treatment.
Sorivudine vs. aciclovir Sorivudine was superior to aciclovir in
reducing the time for new vesicles formation
and total lesion crusting.
Oral brivudin vs. No signicant dierence between the eect
aciclovir (intravenous) of both drugs on new lesions formation or
visceral dissemination.
DPD activity, which recovered after 4 weeks from the
completion of sorivudine therapy. Thus the life-threat-
ening synergistic eect between the two drugs continued
for the following few weeks after the last dose of
sorivudine (83, 84).
Management of post-herpetic neuralgia
Dierent classes of medication have been used for the
treatment of post-herpetic neuralgia. The initial choice
of any of these medications should be guided by the
patients medical health, the likely adverse eects of the
drug and the patients preference. Drugs that are
currently available for the treatment of post-herpetic
neuralgia are rarely associated with complete pain
relief, hence the pharmacological treatment for patients
with post-herpetic neuralgia is considered as a compo-
nent for a more comprehensive treatment approach
which may include various non-pharmacological ther-
apies such as psychological counselling and physical
isolation of the aected area to prevent any provoking
stimuli (85, 86). A recent meta-analysis revealed that
there is evidence to support the use of tricyclic
antidepressants, strong opioids, gabapentin, pregabalin
as well as topical lidocaine 5% patches and capsaicin
for the treatment of post-herpetic neuralgia (87).
Gabapentin and lidocaine patch 5% are considered
to be the rst-line therapies for post-herpetic neuralgia
with opioid analgesics and tricyclic antidepressants
being the second-line treatment. This is because opioid
analgesics and tricyclic antidepressants have poorer
tolerability and require greater caution, particularly in
elderly patients with post-herpetic neuralgia. There are
no data regarding the synergistic benets of the use of
combination therapies for post-herpetic neuralgia,
which may be associated with increase risk of side
eects (86).
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 VZV literature review
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680
Topical analgesics
The use of topical analgesics provides pain relief in post-
herpetic neuralgia with minimum side eects because
these topical agents are formulated to produce local
eect without achieving high plasma concentrations and
hence a reduction in the risk of systemic toxicity and
drugs interactions (88).
Topical lidocaine patches in a 5% concentration have
proven ecacy, tolerability and safety that support its
use as a rst-line therapy in the treatment of post-
herpetic neuralgia either alone or in combination with
systemic agents (8891). Lidocaine patches act as a
targeted peripheral analgesic that should be applied to
the painful skin section, covering as much of the aected
area as possible. Up to three patches can be applied once
daily for a maximum of 12 h day. The most frequent
adverse eects of the lidocaine patches are mild skin
rashes, redness or irritation at the application site.
Systemic lidocaine toxicity has not been reported with
the use of topical lidocaine preparations (92, 93).
Topical application of 0.075% capsaicin cream, a
derivative of hot chilli pepper, three to four times daily
has been reported to provide signicant pain relief when
used for the treatment of post-herpetic neuralgia (89,
94). However, compliance with this treatment is low
because of the intense burning sensation, stinging
and or erythema at the application site. These adverse
eects have limited the number of the placebo-con-
trolled double blind studies undertaken because of lack
of compliance among the treated patients.
Topical application of aspirin dissolved in ether,
chloroform or acetone has been poorly investigated.
Some clinical advantage was observed (40), however, the
extent of this benet, and its safety, is still unclear. In
additon, there is lack of evidence for the benet of
vincristine in the treatment of post-herpetic neuralgia
(95).
The use of sympathetic nerve blocks for the treatment
of post-herpetic neuralgia has been described in several
studies. Despite the benecial eect of sympathetic
nerve blocks in relieving the pain during the acute stage
of shingles, this procedure does not appear to provide
signicant pain relief in patients with long-standing
post-herpetic neuralgia (96).
Anticonvulsants
A number of clinical trials have been undertaken to
investigate the potential role of anticonvulsants in the
treatment of post-herpetic neuralgia (Table 4). Gaba-
pentin is a second generation anticonvulsant that has
proven to be signicantly eective in the treatment of
post-herpetic neuralgia when compared with placebo in
two large controlled clinical trials. In both trials,
gabapentin, at a daily dose of 18003600 mg titrated
over 12 weeks, caused a statistically signicant reduc-
tion in the daily pain rating as well as an improvement in
sleep, mood and quality of life (97, 98). The side eects
of gabapentin include somnolence, dizziness, ataxia and,
less commonly, mild peripheral oedema which may
sometimes require dose adjustment. Moreover, gaba-
pentin may cause or exacerbate abnormal gait, balance
problems and cognitive impairment in elderly people.
Therefore, to reduce the side eects and increase
patients compliance with the treatment, gabapentin
should be initiated at a low dose (100300 mg in a single
dose taken at bed time or 100 mg taken three times per
day) and then titrated by 100 mg three times a day as
tolerated. Because of patients variability in gabapentin
absorption, the nal dose should be determined on the
basis of either pain relief or the appearance of unac-
ceptable side eects that do not resolve over a few weeks
(86, 97, 98).
Pregabalin is a selective high-anity ligand for alpha-
delta subunit protein of the calcium channels, which are

Table 4 Studies for the use of anticonvulsants for the treatment of post-herpetic neuralgia

Total study Duration

References Type of study population Drug used (weeks) Findings
(97) Multicentre randomized 229 Gabapentin titred dose 8 Reduction in the pain score from 6.3 to 4.2
double-blind placebo maximum 3600 mg among gabapentin group and from 6.5 to
controlled 6.0 in placebo recipients
(98) Multicentre randomized 334 Gabapentin 1800 and 7 Change in the pain score from baseline,
double-blind 2400 mg )34.5% for 1800 mg dose, )34.4% for
placebo-controlled 2400 mg dose and )15.7% for placebo
(103) Multicentre randomized 338 Pregabalin xed and 12 Fixed and exible dosage given twice daily
double-blind exible dosage were signicantly superior to placebo in
placebo-controlled pain relief
(102) Multicentre randomized 238 Pregabalin 150 or 8 2628% of the patients in both pregabalin
double-blind 300 mg day groups had 50% decrease in the mean
placebo-controlled pain score than patients in placebo group
(10%)
(104) Preliminary open label 24 Oxcarbazepine 8 Therapy caused a marked reduction in pain
Trial Monotherapy, and allodynia with improvement in the
titred dose maximum quality of life in 84% of the patients
of 900 mg day
(105) Randomized 48 Divalproex sodium 8 58.2% of patients who received divalproex
double-blind sodium had moderate or marked pain
placebo-controlled improvement, in comparison with 14%
patients treated with placebo

J Oral Pathol Med


thought to play an important role in modulating
neuropathic pain. Pregabalin has been developed as a
follow-up compound to gabapentin and it has proved to
be eective in reducing the neuropathic pain by
decreasing the release of neurotransmitters when bound
to alpha-delta subunits (99, 100). In 2004, pregabalin
received both EU and US Food and Drug Administra-
tion (USFDA) approval for the treatment of peripheral
neuropathic pain, which include post-herpetic neuralgia
and diabetic polyneuropathy, and for adjunctive ther-
apy for the treatment of partial seizures in adults (101).
The ecacy of pregabalin in the treatment of post-
herpetic neuralgia was investigated in a randomized
placebo-controlled clinical trial. Oral pregabalin 150
300 mg day administered in two or three divided doses
was superior to placebo in relieving pain and improving
pain related sleep interference in both studies. The drug
was well tolerated by elderly people involved in both
trials. Dizziness, somnolence and peripheral oedema of
mild to moderate intensity were the most common side
eects (102). A more recent study compared the ecacy
and safety of pregabalin, given in a exible dose
schedule of 150, 300, 450 and 600 mg day titrated at
weekly intervals and a xed dose of 300 mg day for
1 week, among patients with post-herpetic neuralgia or
diabetic polyneuropathy. Twice daily administration of
pregabalin either in a exible or xed dosing regimen,
was signicantly superior to the placebo in relieving
chronic neuropathic pain and improving the sleeping
interference associated with post-herpetic neuralgia or
diabetic polyneuropathy. However, rapid onset of
action was noticed with xed dose pregabalin which
may reect the higher dose during the rst week of
treatment with this regime (103).
Recent studies have evaluated the eectiveness and
safety of oxcarbazepine and divalproex sodium (valproic
acid and sodium valproate) for the treatment of post-
herpetic neuralgia (104, 105). In an open-label trial,
oxcarbazepine monotherapy administered for 8 weeks
Table 5 Studies for the use of antidepressants for the treatment of post-herpetic neuralgia
Total study
References Type of study population
(107) Randomized double-blind 35
crossover
(108) Open label crossover 15
study
(109) Randomized double-blind 58
placebo-controlled
crossover
(110) Randomized double-blind 31
placebo crossover
(111) Randomized double-blind 19
placebo-controlled
crossover
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Mustafa et al.
681
resulted in a statistically signicant eect on pain
reduction, allodynia and improvement in quality of life
among patients with post-herpetic neuralgia (104).
Divalproex sodium also resulted in signicant pain
relief in comparison with placebo recipients in a
randomized double-blind study (105). Both drugs were
well tolerated with very few side eects such as dizziness
and nausea. The use of other anticonvulsants such as
phenytoin, carbamazepine, sodium valproate and lamo-
trigine for the treatment of post-herpetic neuralgia is not
supported by the literature (43).
Tricyclic antidepressants
A number of tricyclic antidepressants, such as amitrip-
tyline, desipramine and nortriptyline, have been used for
the treatment of post-herpetic neuralgia based upon
positive ndings from several randomized controlled
trials (Table 5). Tricyclic antidepressants are believed to
exert an analgesic eect unrelated to any antidepressant
eect via inhibition of the neuronal reuptake of norepi-
nephrine and serotonin, which potentiates the inhibition
of spinal neurons involved in pain perception (106).
Clinically, amitryptiline is the most widely used tricyclic
antidepressant for post-herpetic neuralgia, being the
most studied for such treatment and resulting in pain
relief approximately 4766% of patients (107109).
Similar rates of response were found in patients who
received desipramine (63%) and nortriptyline (55%).
The latter was proven to be equivalent in ecacy and
have better tolerability than amitriptyline (110, 111).
Despite the analgesic eect of tricyclic antidepressants
in the treatment of post-herpetic neuralgia, their use has
been limited because of their adverse side eects. Dry
mouth is the most common side eect occurring in
approximately 40% of patients treated with amitripty-
line and 25% of patients treated with nortriptyline.
Constipation, sweating, dizziness, disturbed vision and
drowsiness are reported by as many as 2030% of those
treated with amitriptyline and 515% of those treated
Duration
Drug used (weeks) Findings
Amitriptyline 12.525 mg 12 Pain was releived in 15 patients (37%)
Maprotiline 12.525 mg who were treated with amitriptyline,
and in 12 patients (38%) who
had maprotiline
Amitriptyline 1025 mg 7 Pain was reduced in eight patients
Zimeldine 100300 mg (53%) who were treated with
amitriptyline, and in one patient
(7%) received zimeldine
Amitriptyline 12.5150 mg 6 Pain was reduced in 47% of the
Lorazepam 0.56 mg patients who had amitriptyline, and
in 15% of the patients who were
treated with lorazepam
Amitriptyline 1020 mg 12 Both drugs had similar results
Nortriptyline 1020 mg Pain relief occurred in 21 patients
(67%) who had any of the two drugs
Desipramine 167 mg 6 Pain was reduced in 12 patients (63%)
with desiramine therapy, and in
two patients who had placebo
J Oral Pathol Med
 VZV literature review
Mustafa et al.
682
with nortriptyline. Tricyclic antidepressants should be
used with caution among elderly people with a history of
cardiovascular disease, glaucoma, urinary retention and
autonomic neuropathy (86, 112). The tolerability of
treatment can be improved by gradual dose titration and
the use of more selective tricyclic antidepressants such as
nortriptyline, which seem to have less adverse eects in
comparison with amitriptyline (112). The optimum
duration of tricyclic antidepressant therapy is unknown,
however, it is generally accepted that treatment should
be maintained for several months before attempting
dosage reduction (113).
Opioids
Recently there is increased evidence that patients with
post-herpetic neuralgia may respond to chronic opioid
therapy. In a placebo controlled cross over trial, 38
patients with post-herpetic neuralgia received an average
of 45 mg controlled released oxycodone. Patients
treated with oxycodone had signicantly greater pain
relief and reduction of allodynia compared with those
receiving placebo (114). Opioid analgesics should be
used very cautiously in elderly people with post-herpetic
neuralgia because of the associated risk of side eects
such as constipation, nausea, sedation, cognitive impair-
ment and problems with mobility (86).
In a recent randomized double-blind study, com-
parison of the ecacy and tolerability of two opioids
(slow release morphine and methadone) and two
tricyclic antidepressants (nortryptiline and amitripty-
line) was investigated in patients with post-herpetic
neuralgia. Analgesic ecacy of methadone was com-
parable to amitriptyline and nortriptyline, while slow
release morphine was signicantly greater than nor-
triptyline. Despite the side eects of opioid therapy,
the majority of patients (54%) preferred opioid
therapy to tricyclic antidepressants treatment, proba-
bly because of the greater pain relief experienced with
these agents (115).
Other therapies
A variety of other treatments have been investigated for
reducing the pain and allodynia in post-herpetic neu-
ralgia. These include the use of N-methyl-D-aspartate
receptor antagonists such as ketamine and dextrometh-
orphan, antiviral agents, intrathecal corticosteroids
administration, spinal stimulation and also surgical
removal of the painful skin area. The ecacy of these
methods has not been adequately investigated and some
are only based on case reports (112). However, the use
of intrathecal methylprednisolone has been evaluated in
a recent study involving 277 patients with intractable
post-herpetic neuralgia. Patients were randomized to
receive a preparation of intrathecal methylprednisolone
with lidocaine, lidocaine alone or no treatment. About
90% of the patients who received the combined prep-
aration of methylprednisolone with lidocaine reported
excellent pain relief compared with 6% of those who
received lidocaine and 4% who received no treatment
(116). However, the safety of this approach is still of
concern because of the possible association between this
J Oral Pathol Med
treatment approach and serious side eects such as
aseptic meningitis in patients with pre-existing neuro-
logical disease (112).
Varicella vaccine
The live attenuated varicella vaccine is the rst human
herpesvirus vaccine that is licensed for clinical use in
several countries. Varicella vaccine was rst developed in
Japan in 1974 following extensive passage of a clinical
isolate of VZV, the Oka strain, through human and non-
human cells in vitro (117). Varivax is a monovalent
vaccine that was licensed by the USFDA in March 1995
for use in people 12 months and older. One dose of
vaccine was recommended for children aged 12 months
through 12 years and two doses were recommended for
susceptible adolescents and adults. Use of the vaccine
dramatically decreased varicella morbidity and mortality
(118, 119). However, for additional improvement of
disease control, a second dose of varicella vaccine was
added to the childhood immunization schedule in 2006.
The Advisory Committee on Immunization Practices and
the American Academy of Pediatrics recommended a
universal 2-dose childhood varicella vaccination pro-
gramme (120). The rst dose is recommended routinely at
age 1215 months and the second at 46 years. A second
dose of varicella vaccine among children produces an
improved humoral and cellular immune response that
correlates with improved protection against disease (121,
122). Another vaccine is the ProQuad [measlesmumps
rubella varicella vaccine (MMRV)], which combines the
varicella vaccine with attenuated MMR viruses and was
licensed by the FDA in September 2005 for use in
children 12 months through 12 years of age. Varicella,
measles, mumps and rubella antibody concentrations
after administration of a single dose of MMRV vaccine
are comparable with concentrations after administration
of MMR vaccine and monovalent varicella vaccine
concomitantly at separate injection sites (123).
A number of studies have proved that the live
attenuated varicella vaccine is highly immunogenic and
protective against chickenpox. In a clinical trial under-
taken before licence, children younger than 12 years of
age had a seroconversion rate of about 97% following
administration of a single dose of varicella vaccine with
maintenance of the viral antibodies for 1 year after
immunization (124). Varicella vaccine also produces
T lymphocytes that recognize the VZV proteins. Circu-
lating lymphocytes are present in the peripheral
blood within 2 to 4 weeks after immunization in about
98%100% of healthy children given the vaccine.
Persistence of T lymphocytes has been documented for
up to 6 years following vaccine administration (125).
Adults respond less eectively to varicella vaccine than
children. Achieving seroconversion rate of more than
95% in adults requires the administration of two doses
of vaccine, separated by at least a 4-week interval (126,
127). The cell-mediated immune response and the
persistence of VZV antibodies are lower in healthy
adults who received varicella vaccine than in vaccinated
children. In one study, only 70% of vaccinated adults

had detectable VZV IgG antibodies 26 years after
immunization (128). Varicella vaccine is available for
administration to children with leukaemia who have
been in remission for at least a year and who have an
absolute lymphocyte count of above 700. Vaccination of
these children resulted in higher rates of seroconversion
(95%) following the administration of two doses of
varicella vaccine when compared with single dose
administration (82%) (129).
Varicella vaccine was also found to be highly protec-
tive against chickenpox in several studies undertaken
either before or after licence (130, 131). In a large double
blind, randomized placebo-controlled trial the vaccine
had an ecacy rate of 98% through two chickenpox
seasons, with 95% of the vaccine recipients remaining
free of chickenpox for the following 7 years (130). Some
studies report that chickenpox may still arise in small
percentage of previously immunized children and ado-
lescents, but the infection tends to be milder and
modied to less than 50 skin lesions with lower incidence
of fever in comparison to unvaccinated children (130,
132, 133). In children with acute leukaemia in remission,
the vaccine was associated with high degree of protec-
tion, reducing the attack rate following household
exposure to 13% (129). Fewer studies have evaluated
the ecacy of two doses of varicella vaccine. When two
doses are administered 3 months apart, the estimated
vaccine ecacy over a 10-year observation period for
prevention of any varicella disease has been reported as
98.3%, with 100% ecacy for prevention of severe
disease (121).
Adding varicella to MMR decreases the number
as well as the overall burden of injections. MMRV
(ProQuad) decreased burden would be expected to
enhance compliance and lead to increased rates of
immunization. MMRV was found to be highly immu-
nogenic and eective against clinical disease in a number
of studies (134, 135). However, MMRV vaccine has had
limited availability in the United States since June 2007
because of manufacturing constraints unrelated to
vaccine safety or ecacy and is not expected to be
widely available before 2009 (136).
The live attenuated varicella vaccine was found to be
extremely safe in healthy children and adults. Adverse
side eects such as pain, tenderness and irritation at the
site of injection and rash were minor and transient.
Within 1 month of immunization, about 7% of children
and 8% of adolescents and adults develop mild vaccine-
associated maculopapular rash, which may occur at the
vaccine injection site or elsewhere. Although the Oka
strain VZV was sometimes isolated from some of these
rashes, it is more likely due to the wild type strain
causing these rashes in immunized individuals, probably
reecting chickenpox just acquired before immunity is
gained from the vaccine (137, 138).
It is evident from a number of studies that the
incidence of chickenpox has reduced markedly in the
United States since the introduction of varicella vaccine
in 1995 among all age groups (118, 139). In an active
surveillance undertaken within three communities in the
United States during the period 19952000, varicella
VZV literature review
Mustafa et al.
683
vaccine uptake among children in these areas increased
steadily to 80%. This was associated with a fall in the
annual incidence of chickenpox in children aged 1 to
4 years, ranging from 83% to 90%. More importantly,
the disease incidence fell markedly among infants and
adults, which indicates a reduction in the disease
transmission among these populations. The overall
reduction in the incidence of chickenpox ranged from
76% to 87% (118). Furthermore, an annual hospital-
ization for chickenpox per 100 000 persons also declined
during the period of the surveillance.
As the varicella vaccine contains infectious virus,
there is a possibility for the virus to establish latency
with subsequent reactivation causing shingles. Reacti-
vation of VZV in immunized children with leukaemia
indicates that the vaccine virus can indeed remain latent
in the dorsal ganglia. However, the attack rate for
shingles among these children was signicantly lower
than it was in leukaemic children with natural VZV
infection (140). Very few cases of viral reactivation
causing shingles have been reported among healthy
children and adults who were involved in clinical trials
before vaccine licence. The disease was mild and
treatable with antiviral therapy (141).
It has been suggested that the use of the live
attenuated Oka varicella vaccine in elderly people could
boost their cell mediated immunity to VZV and there-
fore, provide protection against viral reactivation caus-
ing shingles and post-herpetic neuralgia (142). A recent
randomized, double blind, placebo controlled trial
involving 38546 adults aged 60 years or over, was
undertaken to evaluate the eect of vaccination on the
incidence and severity of shingles and post-herpetic
neuralgia. This study showed that the vaccine reduced
the burden of illness due to shingles among elderly
people by 6.1% and reduced the incidence of post-
herpetic neuralgia by 66.5%. Moreover, it showed that
the vaccine reduces the overall incidence of shingles by
51.3% and signicantly reduced pain and discomfort
among those who developed shingles. The results reect
the ability of the vaccine to boost immunity to VZV in
vaccinated individuals (143).
Conclusions
Aciclovir has been the drug of choice for many years for
the treatment of VZV infections. Recently, other antiv-
iral agents have been developed to over come the low
oral bioavailability of ACV as well as to provide a more
attering dosage regime.
Chickenpox is a benign mild self-limiting disease in
the majority of cases and usually no specic treatment is
required. ACV is eective in reducing the severity and
duration of chickenpox if given within 24 h following
the appearance of the skin lesions; moreover, the benet
of using oral ACV in adolescents and adults is more
signicant than in children. The American Academy of
Paediatrics has recommended that it should be consid-
ered for treatment in children 12 years or older, those
with chronic cutaneous or pulmonary disease, those
being treated with short or intermittent courses of
J Oral Pathol Med
 VZV literature review
Mustafa et al.
684
Table 6 Suggested antiviral therapy of primary and recurrent varicella zoster virus (VZV) infection (based upon best available data)
Type of
Disease patient Drug used
VAR Aciclovir
Aa Suspension tablets 1020 mg kg (max 800 mg)
Ba Infusion 500 mg m2
ZOS Aciclovir
A Tablets 800 mg
B Infusion 1020 mg kg
Valaciclovir
A Tablets 1000 mg
B Tablets 1000 mg
Famciclovir
A Tablets 500 mg
B Tablets 500 mg
Brivudin
A Tablets 125 mg
B Not licensed
VAR: Varicella infection; ZOS, Zoster infection.
a
A = immunocompetent, B = immunocompromised.
corticosteroids or aerosol corticosteroids and those
receiving long-term salicylate therapy. The recom-
mended dose is 20 mg kg (maximum single dose of
800 mg) administrated four times a day for 5 days.
Intravenous ACV and vidarabine has been used for the
treatment of chickenpox in immunocompromised chil-
dren and adults.
Treatment of shingles is indicated to reduce the acute
symptoms of pain and malaise, to limit the spread and
duration of the skin lesions and to prevent the devel-
opment of post-herpetic neuralgia and ophthalmologi-
cal complications in herpes zoster ophthalmicus.
Symptomatic treatment of shingles depends upon the
patients condition, the stage of the rash, the harshness
of pain and also upon patients response to antiviral
therapy. Shingles is usually a self-limiting disease and
complete healing occurs when it aects the trunk or the
extremities of young individuals without risk factors.
Antiviral therapy has the benet of shortening the
healing process and seems to be important when a
complicated course of the disease is expected or for
selected patients. ACV is eective in an oral dose of
800 mg, 5 times a day for 7 days but has a limited and
less predictable eect in preventing the development of
post-herpetic neuralgia. Valaciclovir (1000 mg, three
times a day for 7 days) was signicantly more superior
to ACV in shortening the duration of herpes zoster-
associated pain and in reducing the prevalence of post-
herpetic neuralgia as well as the duration of abnormal
sensations. Famciclovir can be used for the treatment of
shingles in immunocompetent people in a dose of
500 mg orally three times a day for 7 days. Brivudin,
given in a single dose orally of 125 mg for 7 days, was
conrmed by many clinical studies to be superior to
other antiviral agents in the treatment of shingles. Thus,
the results of comparative studies of brivudin vs. ACV
and famciclovir showed the importance of brivudin with
respect to reduced total daily dose and a reduced dosing
frequency which provide a more convenient treatment
for elderly patients.
J Oral Pathol Med
Route of
Dose administration Timing
By mouth Four times daily for 5 days
Intravenously Every 8 h as 1-h infusion for 7 days
By mouth Five times daily for 7 days
Intravenously Every 8 h as 1-h infusion for 7 days
By mouth Three times daily for 7 day
By mouth Three times daily for 7 day
By mouth Three times daily for 7 day
By mouth Three times daily for 710 day
By mouth Once daily for 7 days
Dierent classes of drugs have been used for the
treatment of post-herpetic neuralgia. The rst choice
of any of these medications should be guided by the
patients medical health, the likely adverse eects of
the drug and the patients preference. Drugs that are
currently available for the treatment of post-herpetic
neuralgia are rarely associated with complete pain
relief, for this reason the pharmacological treatment
for patients with post-herpetic neuralgia is considered
as a component for a more wide-ranging therapy
approach which may include various non-pharmaco-
logical therapies. Topical analgesics, anticonvulsants,
tricyclic antidepressants and opiods have been found
to be of benect for patiens with post-herpetic
neuralgia.
The aim of this article was to provide a review of
current therapy of VZV infection and Table 6 shows the
suggested protocols for its common clinical presenta-
tions; however, in view of the availability of newer
therapies, there is a need to undertake additional
randomized controlled trials to establish the most
appropriate (and safe) means of treating and preventing
infection in both immunocompetent and immunocom-
promised individuals.
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Acknowledgements
This work was based on a thesis submitted to the postgraduted faculty,
Eastman Dental Institute for Oral Health Care Sciences, University of
London, in partial fullment of the requirements for an MSc degree. A
portion of this work was undertaken at UCL/UCLHT, who received a
proportion of funding from the Department of Health, NIHR Biomedical
Research Centre funding scheme.