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Oral acyclovir therapy of recurrent herpes
simplex virus type 2 infection of the hand.
M J Gill and H E Bryant
Antimicrob. Agents Chemother. 1991, 35(2):382. DOI:
10.1128/AAC.35.2.382.
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Vol. 35, No. 2
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Feb. 1991, p. 382-383
0066-4804/91/020382-02$02.00/0
Copyright C) 1991, American Society for Microbiology
Oral Acyclovir Therapy of Recurrent Herpes Simplex Virus Type 2
Infection of the Hand
M. JOHN GILLl* AND H. E. BRYANT2
Departments of Microbiology and Infectious Diseases and Medicine' and Department of Community Health Sciences,2
University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada
Received 1 August 19%/Accepted 10 December 1990
=
were assessed daily on a comparative basis (worse,
same, better, or gone). The episode was classified as being
Effective treatments for most human herpes simplex virus
(HSV) infections have been well documented (7, 9-12).
However, recurrent HSV infection of the band, which can
be frequent, painful, and cosmetically unacceptable, has
attracted little therapeutic attention (1-3, 5, 6, 8). After an
earlier uncontrolled observation, we evaluated in this double-blind, placebo-controlled crossover study the effects of
early intervention with oral acyclovir on the durations of
symptoms, signs, and virl culture positivity of recurrent
HSV type 2 (HSV-2) infection of the hand (4).
Fourteen patients (11 males and 3 females) with documented HSV-2 infection of the hand participated in a study
that was approved by the University of Calgary Committee
on Medical Bioethics. All the patients were between 18 and
50 years old and had between 2 and 12 recurrent infections
per year. They were otherwise in good health with no
evidence of any underlying immunodeficiency. All the females were using a recognized form of contraception and
were not pregnant at the time of treatment.
A double-blind, placebo-controlled crossover design was
adopted in view of the limited number of eligible patients.
Due to uncertainties about the bioavailability of acyclovir at
the time of the study design, a high-dose regimen was
selected. Active drug or placebo (provided by Burroughs
Weilcome, Kirkland, Quebec, Canada) was randomized to
either cycle A or B by a computer program. The patients
were given written instructions and a bottle of 100 tablets
(cycle A). They were advised to take four tablets when
prodromal symptoms which they felt likely to result in HSV
infection of the hand were first noticed, followed by two
doses each of three tablets in a 24-h period. A total of 10
tablets per day in three doses was given for a total of 10 days.
The patients were reviewed within 24 h of initiating therapy
and then daily until the episode resolved. After the first
course of therapy, the patients returned the cycle A bottle
and were given a second bottle (cycle B) with identical
instructions.
The presence and severity of symptoms (pain, swelling,
tingling, tenderness, and discomfort) and both local and
systemic signs of infection (erythema, papule, vesicle, pustule, scab, lymphangitis, and lymphadenopathy) were recorded at each visit. Symptoms were classified on the initial
visit by the patient as being mild, moderate, or severe and
*
then
resolved when both the symptoms and signs had disappeared. Whenever a papule, vesicle, pustule, or scab was
present, samples for viral culture were taken. After the skin
was cleaned with alcohol, a 25-gauge needle was used to
release fluid, and the lesions were swabbed with a Dacrontipped applicator. The samples were placed in standard viral
transport medium, refrigerated at 4°C, and planted on HeLa
and/or human embryonic lung cells within 72 h. At each
visit, the patients were questioned about any side effects. No
adverse effects were recognized during either phase of the
study.
Descriptive statistics of central tendency (mean values)
were calculated by using the MINITAB statistical program.
Comparisons between acyclovir and placebo therapy were
analyzed by using within-patijnt paired t tests.
Before participating in the first arm of the protocol, one
female (no. 11) and one male (no. 5) withdrew because of a
family relocation and a job transfer, respectively. One patient (no. 14) failed to develop any recurrences that could be
monitored during the 1 year of observation prior to the
termination of the study. One patient (no. 8) completed cycle
A (acyclovir) and was lost to follow-up for cycle B. During
cycle A, the patient's durations of symptoms and signs were
5 and 3 days, respectively, and no virus was isolated. One
patient (no. 2) completed cycle A (acyclovir) and withdrew
since she wished to become pregnant. During cycle A, the
patient's durations of symptoms and signs were 1 and 4 days,
respectively, and no virus was isolated. Nine patients completed both arms of the study.
All the patients were instructed to initiate therapy as soon
as a prodrome suggestive of an attack was noted. Despite
describing long prodromal phases in the past, most patients
initiated therapy at a time very close to the appearance of
clinical signs (9 h for placebo versus 4 h for acyclovir; P =
0.14). A reluctance to initiate therapy for a 10-day clinical
trial without being absolutely certain the symptoms would
progress into clinical signs or no immediate access to the
drug supply were commonly cited as excuses for this delay.
The results of the study are shown in Table 1. The mean
duration of symptoms for the entire episode from initial
prodrome to complete resolution of symptoms was 10.1 days
in the placebo-treated group, compared with 3.7 days in the
acyclovir-treated group (P = 0.008). The time to first subjective improvement in symptoms was reduced from 4.3 to
Corresponding author.
382
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Acydovir was evaluated as treatment of recurrent herpes simplex virus type 2 infection of the hand in a
double-blind, placebo-controed crossover study. In nine fully evaluable patients, oral acyclovir (2 g/day in
three doses for 10 days) initiated during the earlist phase of a recurrence reduced the mean durations (±
standard deviation) of clinkal symptoms from 10.1 (±3.6) to 3.7 (±3.0) days (P = 0.008), signs from 11.1
(±3.7) to 6.2 (±3.3) days (P 0.024), and viral positivity from 5.3 (+3.8) to 0.6 (±1.1) days (P = 0.011).
VOL. 35, 1991
NOTES
TABLE 1. Durations of symptoms, signs, and viral culture
positivity during placebo and acyclovir treatment courses
Duration (no. of days) of:
Patient
Symptoms
Signs
Viral positivity
Placebo Acyclovir Placebo Acyclovir Placebo Acyclovir
1
3
4
6
7
9
10
12
13
2
3
7
2
1
5
10
3
1
10.1
3.6
P value'
3.7
3.0
0.008
14
10
14
7
13
5
10
10
17
10
5
10
6
5
5
10
5
Nil
11.1
3.7
6.2
3.3
0.024
4
4
4
4
7
2
4
4
15
5.3
3.8
Nil
Nil
Nil
2
Nil
Nil
3
1
Nil
0.6
1.1
0.011
a Paired t comparison.
1.2 days (P
=
0.003). For almost all patients, the duration of
symptoms and time to symptomatic improvement were
shorter during the acyclovir treatment than during the placebo treatment.
The mean duration of objective signs in the placebotreated group was 11.1 days, compared with 6.2 days in the
acyclovir-treated group (P = 0.024). In every case, the
duration of signs was shorter when the patients were receiving acyclovir therapy.
The mean difference in durations of viral shedding between the two study groups was statistically significant (5.3
versus 0.6 days; P = 0.011). Specimens from seven of the
nine patients receiving therapy with oral acyclovir were not
positive in viral culture. For two patients (12 and 6), viral
cultures were positive- at the initial and second visits only. In
patient 13 during the placebo-treated episode, HSV was
present from visits 1 to 9 and 11 to 15, representing what
appeared clinically to be two recurrences in rapid succession.
In this study, a total daily dose of 2 g of oral acyclovir was
found to be effective in reducing the durations of symptoms,
signs, and viral positivity when initiated during the early sign
of a recurrence of HSV-2 infection of the hand. However,
the dosage of acyclovir, duration of therapy, and timing of
intervention can likely be further optimized to give results
equal or even superior to those described above. Other
studies have suggested that lower doses of acyclovir are
effective in the early treatment of recurrences of HSV-2
infections at other sites (10). The 10-day course of therapy
was chosen to be longer than the anticipated duration of a
recurrence. Since acyclovir shortened the duration of an
episode to around 5 days, a 10-day course of therapy appears
to be excessive in most situations. It is also possible that
earlier intervention during the prodromal phase of a recurrence may achieve greater clinical effects.
Although the vast majority of recurrent HSV infections of
the hand are HSV-2, HSV-1 infection of the hand is occasionally recurrent (3). Studies of recurrent HSV-1 infections
of the lips suggest that they, too, respond to such treatment
(9). Unfortunately, due to the relative rarity of patients with
such infections, controlled studies of HSV-1 infection of the
hand may be impractical.
In summary, oral acyclovir administered during the early
stages of recurrent HSV-2 infection of the hand had a
beneficial effect on the durations of symptoms, signs, and
viral positivity.
This study was supported in part by a grant from Burroughs
Wellcome Canada Ltd.
We thank D. L. Tyrrell for his assistance and encouragement
during the study and Bonnie Williams for typing the manuscript.
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Mean
SD
14
10
14
5
13
5
7
10
13
383