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Current experience with antiviral therapy for acute herpes zoster.

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Current Experience with Antiviral Therapy
for Acute Herpes Zoster
Martin J. Wood, FRCP
Inhibition of varicella-zoster virus replication during acute herpes zoster would, theoretically, accelerate cutaneous
healing and reduce the pain, both acute and chronic, associated with shingles. Early antiviral drugs were of limited
efficacy, excessively toxic, or needed to be given parenterally, and were unsuitable for use in immunocompetent
individuals. Acyclovir was a significant advance and remains the antiviral drug of choice for herpes zoster. There is
ample evidence for its efficacy in acute illness, but its ability to influence post-herpetic neuralgia is controversial. This
review also discusses the role of adjunctive therapy with steroids in acute shingles.
Wood MJ. Current experience with antiviral therapy for acute herpes zoster. Ann Neurol 1994;35:S65-S68
Any therapy for herpes zoster is intended either to
decrease symptoms and promote healing of the skin
rash during the acute phase of the illness, or to diminish the incidence or severity of any complications,
particularly post-herpetic neuralgia (PHN), the most
frequent and troublesome problem. A number of
approaches, some bizarre and ill-conceived, were tried
for the therapy of shingles, but it was only with the
relatively recent development of antiviral drugs with
activity against varicella-zoster virus (VZV) that any
success was achieved.
domized trials with closely matched control subjects.
It is unfortunate that many trials were too small or did
not define the groups of patients in sufficient d e t d for
their compatibility to be assessed.
Older Treatments
In the first half of the century, a number of treatments
were used without ever being tested in a controlled
trial, and although each had its advocates, any success
probably owed more to a placebo effect than to science. These “remedies” include injections of posterior
pituitary extract, B vitamins, quinine, cobra venom,
proteolytic enzymes, sodium iodide and ergotamine,
and autohemotherapy {l, 21. A number of anesthetic
approaches have also been advocated. Sympathetic and
somatic nerve blocks do seem to relieve the acute pain
of shingles but the suggestion that sympathetic blockade limits P H N still needs confirmation r3, 41.
The introduction of compounds effective against
herpesviruses (Table 1 ) was accompanied by great optimism that the pain associated with herpes zoster could
be significantly improved. However, the incidence and
intensity of the acute pain of herpes zoster and the
incidence of any complications vary considerably between patients, depending on the dermatomal distribution of the rash and the age of the individual. It is of
paramount importance, therefore, that any new treatment for herpes zoster is judged in double-blind, ran-
The first of the anti-VZV agents to be evaluated in
shingles was topical idoxuridine (IDU), formulated in
a dimethylsulfoxide (DMSO) base, which was licensed
for use in Europe but not in the United States. When it
was administered to otherwise healthy patients [S-81,
however, the results and conclusions drawn were
somewhat conflicting and difficult to interpret, largely
due to deficiencies in study design. The initial study
[G} suggested that a 5% IDU solution was not clearly
effective but that by using a 40% solution applied constantly to the whole of the affected dermatome (by
soaking a piece of lint cut to shape), significant benefits
on healing and acute pain as well as the development
of PHN could be obtained. A later study [5] concluded that intermittent therapy with 5% or 25% IDU
in DMSO was equally effective. Each of these studies,
however, suffered from design problems; either the
comparability of rash distribution in the treated and
placebo groups was uncertain or noncontrolled patients
were included in the statistical analysis. More recently,
two trials from Scandinavia f?, 8} added further confusion. The first suggested a benefit on rash healing, but
not on pain, from 40% IDU in DMSO solution (but
not ointment) applied to lint, but it was accepted that
there was not strict comparability between the distribution of the rash in the patient groups studied [?I. In a
subsequent trial this was rectified and 40% IDU solution was shown to have no effect overall on P H N [S}.
Rather surprisingly, however, when the 42 patients
From Birmingham Heartlands Hospital, Birmingham, United Kingdom.
Address correspondence to Dr Mood, Birmingham Heartlands Hospital, Bordesley Green East, Birmingham, B9 5ST, United Kmgdom.
Copyright 0 1994 by the American Neurological Association S65
Table 1. Drtlgx u?ith Antivirul EfJicacy Aguinst
Varicella-Zo.rter V i r u
Cytosine arabinoside (cytarabine)
Adenosine arabinoside (vidarabine)
with uigeminal zoster were compared with the 80 with
thoracic zoster, IDU shortened the duration of pain,
but not the sensitivity changes in the skin, in the former but not the latter group 18). Given the uncertainties and impracticality of a patient with trigeminal zoster
covering the affected dermatome with a piece of lint
and keeping it soaked with IDU solution for 5 days,
topical IDU is not a very practical approach, even in
those countries where it is available.
Cytosine Arabinoside
Cytosine arabinoside was only rarely used intravenously in normal patients with zoster since it was soon
shown to be harmful in controlled studies in the immunocompromised {91. Even when given subcutaneously
to normal persons, cytarabine was not helpful, leading
to prolongation of the rash and new symptoms {lo}.
Adenine Arabinoside
In a randomized, double-blind, placebo-controlled
study of 5 days of intravenous vidarabine in immunosuppressed patients with herpes zoster, there was a
more rapid resolution of acute pain in the vidarabinetreated group f 1If. The duration but not the incidence
(45% in each group) of P H N was also reduced: 4
months after the onset of the infection, P H N was recorded in 44% in the treatment group versus 83% in
the placebo group ( p = 0.047). Although vidarabine
may thus be useful in the immunocompromised host,
its toxicity has prevented any controlled trials of its use
in otherwise healthy patients with zoster.
Intramuscular interferon has been given to immunocompromised persons with shingles, and some success
in reducing acute pain and both the incidence and the
duration of P H N was reported in one study of human
leukocyte interferon { 121 but not in another of recombinant interferon-a [13f. Furthermore, although interferon has been given with success to normal persons
with shingles, the study was neither satisfactorily randomized nor double-blind [ 141, and conclusions regarding any potential for interferon in this setting cannot be made.
The principal antiviral agent studied in herpes zoster
is acyclovir. Initial studies in herpes zoster were under-
taken using the intravenous compound in immunosuppressed patients: Therapy with intravenous acyclovir
for 1 week was highly effective at preventing progression of the rash {15}. There was also a reduction in
acute pain and in PHN-although
the differences
were not significant. Studies of the intravenous preparation in immunocompetent patients C16-2 11 produced similar results-some efficacy against the acute
pain but no significant effects on P H N (Table 2) 1221.
One feature of note was that acyclovir recipients in
some of these studies 117, 181 noted a worsening of
their pain after 5 days’ therapy was stopped, suggesting
that longer courses of therapy might be better.
When an oral formulation of acyclovir became available, it was obviously of great potential as a therapy
for ambulatory patients with shingles. The initial studies were undertaken with 400-mg doses given five
times daily {23-251. The first of these studies [231,
however, did not compare oral acyclovir with placebo
and those that did showed little evidence of any antiVZV effect and no effect on either acute pain or PHN.
A higher dose of oral acyclovir (600 mg, five times
daily given for 10 days) was studied in a double-blind
trial in 7 1 immunocompetent patients with ophthalmic
herpes zoster; acute pain was reduced by acyclovir but
again no effect on P H N was seen 1261. The study did
demonstrate, however, that this dosage of oral
acyclovir significantly reduced the incidence and severity of the most common ocular complications of ophthalmic zoster, even when therapy was started 7 days
after the onset of the characteristic skin rash.
There have now been four published studies of the
efficacy of higher oral doses of acyclovir (800 mg given
five times daily) in apparently immunocompetent patients with acute herpes zoster [27-301. All showed
that acyclovir therapy significantly reduces the duration
of the rash and alleviates pain during the acute illness.
There are, however, differences reported when the effects on P H N are analyzed. The largest study, from
England [28, 31), was limited to patients over the age
of GO years and found no evidence of a reduction in
the incidence of P H N overall or in any particular subgroup of patients 1311. Patients in this study were
treated for 7 days. After the acute phase, however,
patients were only seen monthly until they admitted
to no pain since the previous visit, and it is possible
that some patients may have had a late recurrence of
their pain. In another large trial performed in the
United States [27), patients of any age were treated
for 10 days and analysis of P H N data was rather more
detailed. The type of pain was recorded and an attempt
was made to contact all patients for the full 6 months
of follow-up (although about one fourth of the patients
were not followed beyond 3 months). The initial report
of this study indicated that there was significantly less
pain in the acyclovir-treated group for the first 3
S66 Annals of Neurology Supplement to Volume 35, 1994
Table 2. Intravenous Acyclovir in Nomal Patients with Herpes Zoster: Efects on PoJt-Herpettc Neuralgta (PHN)a
Acyclovir (A)
with PHN (n):
with PHN (n):
Placebo (P)
31 (17)
37 (27)
12 (16)
40 (20)
50 (10)
14 (29)
26 (17)
50 (20)
% Difference
Intervals (%)
+ 17
-19 to +56
-45 to -01
-12 to +37
-21 to +41
- 23
+ 14
+ 10
“Adapted from Schmader and Studensh [221
months of follow-up (although the results were analyzed with one-tailed tests of significance and significance was lost if a two-tailed test was used). The benefit
of acyclovir was most marked in those patients with
the chronic persistent form of pain. There was, however, no difference in the frequency of any type of
pain during months 4 to 6. A study in New Zealand
[29} of 83 adults with acute herpes zoster (some of
whom were given steroids or mood-enhancing therapy), treated for 7 days with acyclovir 800 mg five
times daily (the same regimen as in the United Kingdom [UK] study), showed that the group given
acyclovir had less P H N than did the placebo group
for the first 2 months after the rash had healed. The
differences between acyclovir and placebo were significant for the second and third months of follow-up
[29). Unfortunately, there were no data on the numbers of patients in the two groups taking corticosteroids, other antiinflammatory drugs, or antidepressants. An analysis of all the controlled studies of oral
and intravenous acyclovir therapy for herpes zoster in
immunocompetent patients published up to 1988 (but
excluding the New Zealand study) [22} concluded that
when the results were pooled (having first been formally tested for homogeneity), the results failed to confirm an effect of acyclovir on PHN.
More recently, a further review of the efficacy of
oral acyclovir in herpes zoster has been undertaken
{32). This overview had the advantage of a further
analysis of the results from the large UK and US studies (as well as the two studies 129, 30) published since
the review by Schmader and Sudenski {22}). The end
points used for statistical analysis were the time to first
cessation of pain and the time to complete cessation of
pain (Table 3). For first cessation of pain, a statistically
significant benefit of acyclovir was found for the US
study only and the pooled data did not reach significance. When time to complete cessation of pain was
analyzed, however, there was a highly significant effect
of acyclovir, with the duration of pain shortened from
an average of 86 days to 49 days ( p < 0.001). The
large UK study { 3 I) could not be included in this latter
analysis, since only the tune to first cessation of pain
was recorded in the study. The authors [32) concluded
that “oral acyclovir does have a beneficial effect upon
Table -3. Mean Pain Duration (days) in Oral Aqclwir Trials“
> 0.1
> 0.1
> 0.1
< 0.001
Time to 1st cessation
of pain
US 127)
New Zealand E291
UK E301
UK E3 1)
Time to complete
cessation of pain
US [27]
New Zealand [27]
UK c301
UKb 1311
‘Adapted from Crooks et al. I321.
bTime to first cessation of pain for comparison.
PHN” but given that some details of the analysis are
not yet available, perhaps at this stage it would be fairer
to suggest that the evidence is encouraging but not
Another question that still remains unanswered is the
place of corticosteroids in the treatment of acute shingles. A number of studies have attempted to determine
a role for such therapy, particularly in preventing
PHN. An uncontrolled study of subcutaneous triamcinolone given into the sites of the rash or acute pain
“until the desired results were achieved” seemed to
show a benefit on P H N [33}, but the drawbacks to
the use of retrospective controls are obvious. Another
small trial (40 patients over 50 years old) compared
oral prednisolone with carbamazepine in a nonblinded
fashion {34}, and although there was a reduction from
65% to 15% in the incidence of pain that lasted for
more than 2 months, the comparability of the treated
and placebo groups with respect to the distribution and
severity of disease is unclear, the trial was not doublcblind, and whether carbamazepine might have had a
detrimental effect is not considered. One controlled
study in a small number of patients over 60 years old
did suggest that oral triamcinolone in high dosage for
Wood: Antiviral Therapy for Acute Herpes Zoster S67
3 weeks accelerated the resolution of PHN {35}. The
5. Balfour HH, Bean B, Laskin OL, et al. Acyclovir halts progres-
best-designed study of corticosteroids, however, combined them with acyclovir and compared this with
acyclovir alone C363. In this study, assessment of the
patients 6 months after the onset of their illness
showed that there was no benefit from steroid therapy
in the rate of PHN, although steroids did seem to
reduce the pain during the first 3 days of therapy (at
the time of the maximal inflammation).
The results of the studies of the effects of steroids
alone and in combination with antiviral agents currently being undertaken in the UK and US are needed
before a firm conclusion can be reached about the optimal therapy in acute herpes zoster.
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