Accepted Manuscript

Title: Randomized clinical trial of famciclovir or acyclovir for

the treatment of herpes zoster in adults.

Authors: Henrique Pott Junior, Monalisa F.Bocchi de Oliveira,

Sheley Gambero, Roberto Bleuel Amazonas

PII: S1201-9712(18)34408-4
DOI: https://doi.org/10.1016/j.ijid.2018.04.4324
Reference: IJID 3230

To appear in: International Journal of Infectious Diseases

Received date: 2-2-2018

Revised date: 27-4-2018
Accepted date: 30-4-2018

Please cite this article as: Pott Junior Henrique, de Oliveira Monalisa FBocchi, Gambero
Sheley, Amazonas Roberto Bleuel.Randomized clinical trial of famciclovir or acyclovir
for the treatment of herpes zoster in adults.International Journal of Infectious Diseases
https://doi.org/10.1016/j.ijid.2018.04.4324

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 1

Title page

Title. Randomized clinical trial of famciclovir or acyclovir for the treatment of herpes zoster in
adults.

Running Title. Famciclovir or acyclovir for the treatment of herpes zoster in adults.

Author names and affiliations.

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Henrique Pott Junior 1*

Monalisa F. Bocchi de Oliveira 2

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Sheley Gambero 2

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Roberto Bleuel Amazonas 2

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1
Federal University of São Paulo
2
NC Farma Group

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*Corresponding author.

Henrique Pott Junior

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E-mail: henriquepott@gmail.com
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Present/permanent address. Rod. Jornalista Francisco Aguirre Proença, s/n - Chácara Assay, CEP:
13186-901 Hortolândia – São Paulo, Brasil.
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Highlights
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Famciclovir and Acyclovir are not different enough to be clinically relevant for the treatment
of uncomplicated herpes zoster.
The mean time to achieve complete cure is 15 days for Acyclovir and 14,8 for Famciclovir.
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Both treatments showed similar proportion of patients who achieved complete cure.
The assessment of intensity scores for pain, vesicular lesions, loss of sensibility, burning pain
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and pruritus over the follow-up period showed no statistically significant difference between
the two treatment groups.
Famciclovir and Acyclovir are safe. Adverse events were consistent with those reported in
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previous clinical trials, and all adverse events reported or observed during the study were
mild, transient and did not result in any clinical impact.

Abstract

Background. This study investigated the safety and effectiveness of famciclovir compared to
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acyclovir in patients with herpes zoster to determine if both regimens are equally suited to

treat uncomplicated herpes zoster patients for 7 days.

Methods. Patients were randomly assigned to receive either Famciclovir 500 mg (one tablet)

t.i.d. or Acyclovir 800 mg (two capsules) five times daily for 7 days. The primary endpoint was

defined as the time to full crusting of herpes zoster lesions. Secondary endpoints were the

proportion of patients who achieved complete cure and the score evolution of signs/ symptoms

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(pain, vesicular lesions, loss of sensibility, burning pain and pruritus) according to the diary. This

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study is registered at the ClinicalTrials.gov: NCT01327144.

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Results. 174 patients were enrolled and randomized, and 151 completed treatment (n=75

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famciclovir, and n=76 acyclovir). Similar proportion of patients who received Acyclovir (94.74%)

and Famciclovir (94.67%) achieved complete cure. The mean time to full crusting of herpes

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zoster lesions was 15.033 days and 14.840 days for the Acyclovir and Famciclovir, respectively
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(log-rank p-value = 0.820). The most common adverse events in the pooled groups were
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headache, diarrhea, nausea, back pain, cold and drowsiness, but none of these was deemed to
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be clinically important.

Conclusions. Both interventions obtained high rates of cure and similar time to full crusting of
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lesions. The analysis of primary efficacy endpoint proved that Famciclovir is non-inferior to
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Acyclovir, as the confidence interval for the difference in efficacy did not violate the non-inferior

margin. Therefore, the results are not different enough to be clinically relevant.
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Keywords: Herpes zoster, Acyclovir, Famciclovir, Randomized controlled trial.

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Introduction
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Herpes zoster (HZ) or shingles is a clinical syndrome resulting from the reactivation of the latent

varicella-zoster virus within the sensory ganglia, manifesting as a unilateral vesicular skin

eruption involving one to three dermatomes. 1,2

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Approximately 1 out of every 3 people will present an episode of shingles during their lifetime.

The number of new cases per year varies between 1.2-3.4 per 1000 people among healthy adults

and 3.9-11.8 per 1000 people among those over 65, reaching 4.5 / 1000 person-years above 75

years. 5–11 According to an epidemiological study conducted in Brazil, 95% of adults have already

been exposed to the varicella-zoster virus. 11 Although it is more common among the elderly, HZ

can occur at any age, provided that the individual has already been infected by VZV.

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In the course of viral reactivation, the virus spreads centrally and peripherally, from the dorsal

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ganglia producing intense inflammation in the skin, affecting peripheral nerves and nerve roots,

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and can also reach the spinal cord. The vesicular rash is often painful and can occur before the

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onset of rash, or, in rare cases without developing rash (herpes sine herpete). 3–6

Thus, the management of uncomplicated HZ involves antiviral therapy to promote faster healing

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of cutaneous lesions and, in patients with moderate to severe acute neuritis, analgesic
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treatment may be associated. Famciclovir, the oral prodrug of penciclovir, belongs to the same
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family of anti-herpetic agents as acyclovir and valaciclovir (oral prodrug of acyclovir), but has
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different pharmacokinetic and antiviral properties.18 Although penciclovir and acyclovir appears

to have similar effects in VZV-infected cells, penciclovir-triphosphate persists far longer than
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acyclovir-triphosphate resulting in more prolonged antiviral activity. 14

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This study investigated the safety and effectiveness of famciclovir compared to acyclovir in

patients with HZ to determine if both regimens are equally suited to treat uncomplicated HZ
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patients for 7 days.

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Patients and Methods

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Design overview

This was a multicenter-center, single-blind, active-controlled, parallel-group, non-inferiority

phase 3 study to compare the efficacy and safety of Famciclovir and Acyclovir in

immunocompetent adults with uncomplicated HZ. Patients were followed for 28 days with
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intermediate visits during days 7 and 14. The study was conducted in accord with the ethical

principles originating in the Declaration of Helsinki, and the protocol was approved by the ethics

committees of all participating sites. All patients provided written informed consent to

participate. (ClinicalTrials.gov: NCT01327144)

Participants

Patients were enrolled if they met the following criteria: immunocompetent adults older than

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18 years with uncomplicated HZ and with 40 mm or more on the visual analog scale (VAS) for at

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least two symptoms/ signs: pain, loss of sensibility, burning and pruritus. Uncomplicated herpes

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zoster infection was defined as an unilateral vesicular rash, that affects 1–3 adjacent

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dermatomes, often accompanied or preceded by pain. Key exclusion criteria included: clinical

diagnosis of severe infection of HZ, history of hypersensitivity to famciclovir and acyclovir,

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previous use of antiviral drugs or corticosteroid therapy, severe systemic disease, and breast
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feeding or pregnancy.
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Randomization and intervention
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Eligible patients were randomly assigned (1:1) to either Famciclovir 500 mg (one tablet) t.i.d. or

Acyclovir 800 mg (two capsules) five times daily according to a computer-generated

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randomization code. All therapy was given orally for 7 days.

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Study assessments

Efficacy. After the baseline assessment, lesions were evaluated by the investigator after 7 days
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of treatment, and at day 7 and 21 post-therapy. The primary endpoint was defined as the time
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to full crusting of HZ lesions. Secondary endpoints were the proportion of patients who achieved

complete cure and the individual score evolution of signs/ symptoms (pain, vesicular lesions,
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loss of sensibility, burning pain and pruritus) according to the diary. Each signs/ symptoms was

evaluated once daily for 28 days based on a visual analogue scale. Each patient self-administered

the questionnaire, filling out the form before the beginning of the treatment and then every

day, on the basis of symptoms in the previous 24 hours.

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Safety. Serum electrolytes, liver enzymes, creatinine, full blood count were performed at

admission and before outpatient discharge. Decisions regarding discharge were made on an

individual basis after substantial improvement of symptoms.

Statistical Methods

For all efficacy endpoints, statistical analyses were performed in the per protocol (PP)

population that included patients who were more compliant with the protocol.

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Sample size was estimated to detect non-inferiority between each Famciclovir and Acyclovir

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for the difference in the log of the cure rate of participants reaching the primary endpoint,

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presuming a log(1,20) of participants have treatment success in the Acyclovir therapy group

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and a one-sided alpha of 0.025. Assuming a dropout rate of 10% after randomization, 76

randomized patients per group (152 total patients) was estimated to provide at least 80%

power to exclude a non-inferiority margin of - log(1,50). U

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All analyses were conducted using R 3.4.3 (The R Project for Statistical Computing, 2017) in R-
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studio 1.0.136 (RStudio Inc., Boston, USA)
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Results
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A total of 174 patients were enrolled and randomized, and 174 started treatment between
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December 2015 and July 2017. Twenty-three patients were discontinued. (Figure 1) Common

reasons for discontinuation were mainly on loss of follow-up (2 acyclovir, and 3 famciclovir),
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withdrawal of consent (3 acyclovir, and 2 famciclovir), and protocol violation (4 acyclovir, and 6
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famciclovir). Other reasons included lack of adherence (1 famciclovir), adverse event (1

famciclovir), and investigator's decision (1 acyclovir).

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Figure 1.

There were no clinically meaningful differences among treatment groups in patient

characteristics at baseline (Table 1). More than half of the patients were female (64.9%). The

median age was 59 years (range 18 − 92), and the mean baseline visual analog scale for the
 6

symptoms/ signs were 6.16 ± 2.86, 6.43 ± 1.88, 3.59 ± 3.31, 6.26 ± 2.90 and 5.34 ± 3.45, for pain,

vesicular lesions, loss of sensibility, burning pain and pruritus, respectively.

Table 1.

Efficacy

The distribution of each efficacy parameter was estimated by Kaplan-Meier, the differences

between the treatments were determined using Cox's proportional hazards model considering

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treatment, age, sex, and baseline pain as co-variables. The mean time to full crusting of HZ

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lesions was 15.033 days and 14.840 days for the Acyclovir and Famciclovir, respectively (log-rank

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p-value = 0.820). (Figure 2)

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Figure 2.

Secondary outcomes

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Similar proportion of patients who received Acyclovir (94.74%) and Famciclovir (94.67%)
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achieved complete cure (Table 2). The difference in complete cure rates between Acyclovir and
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Famciclovir was 0.07% (95% CI was -7.18 to 7.32%). Therefore, non-inferiority of Famciclovir to
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Acyclovir was verified according to this analysis.

Table 2.
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Individual VAS score evolution of signs/ symptoms (pain, vesicular lesions, loss of sensibility,
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burning pain and pruritus) was assessed at each visit and patient diary entry. (Table 3.)

Table 3.
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Safety
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Adverse events (AEs) were consistent with those reported in previous clinical trials of famciclovir

and acyclovir, and no additional or unique adverse events occurred.

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Overall frequencies of adverse events were similar in the two groups during the entire

treatment. There were 142 episodes of adverse events, of which 79 episodes (55.63%) in the

Acyclovir group and 63 episodes (44.37%) in the group treated with Famciclovir. No serious,

grade 2, grade 3, or grade 4 adverse events were identified in participants of either groups. The
 7

most common AEs were headache in 49 patients, diarrhea (9), nausea (8), back pain (6), cold (6)

and drowsiness (4), but none of these was deemed to be clinically important.

All adverse events reported or observed during the study were mild, transient, subsided without

specific interventions and did not result in any clinical impact. No clinically significant laboratory

abnormalities were identified in any patient.

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Discussion

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The present study that investigated the safety and efficacy of Famciclovir or Acyclovir

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demonstrated that both interventions obtained high rates of cure and similar time to full

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crusting of lesions. The analysis of primary efficacy endpoint proved that Famciclovir is non-

inferior to Acyclovir, as the confidence interval for the difference in efficacy did not violate the

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non-inferior margin. Therefore, the results are not different enough to be clinically relevant.
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After 28 days of treatment, VAS score evolution of vesicular lesions fell to zero in both
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treatments, demonstrating the efficacy of the treatments. Other symptoms (loss of sensibility,
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burning pain and pruritus) measured by VAS during the follow-up period also dropped to zero,
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corroborating the efficacy of both treatments, with no statistical difference.

At the end of follow-up, of the 76 patients in the Acyclovir group who completed the study, 72
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of them had completely cured, with a mean time to achieve complete cure of 15.033 days. For

the Famciclovir group, of the 75 patients who completed the study, 71 had completely cured,
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with a mean time to achieve complete cure of 14,840 days. The data presented above
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corroborate the observation of shortening the time to achieve complete cure through the use

of antivirals. In addition, treatment with Famciclovir may be considered non-inferior to Acyclovir

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in time to full crusting of lesions, as the upper limit of the 95% CI for the difference between the

log of the cure rate for the Famciclovir and Acyclovir groups is less than the established margin.

Nonetheless, pain is the most common symptom of shingles, affecting approximately 75% of

patients in the form of altered sensitivity or pain circumscribed to the involved dermatome
 8

where the rash will appear later.17 In the course of viral reactivation, acute hyperalgesia is usually

the first symptom and occurs in approximately 70-80% of patients. Also, type and intensity of

pain may vary over time, persisting at all stages of the disease.17 Before starting the study, the

mean score in the subjective assessment for the pain symptom was 6.11 mm ± 2.95 mm and

6.25 mm ± 2.86 mm for the treatment groups Acyclovir and Famciclovir, respectively. For the

burning pain symptom, similar results (6.05 mm ± 2.79 mm and 6.73 mm ± 2.96 mm for the

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Acyclovir and Famciclovir groups, respectively) were found. The evaluation of intensity of

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symptoms recorded through VAS showed that the study population experienced moderate to

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severe acute pain during the viral reactivation episode.

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Thus, the management of uncomplicated HZ involves antiviral therapy and, in patients with

moderate to severe acute neuritis, analgesic treatment may be associated. For such, antiviral

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agents such as famciclovir, valaciclovir and acyclovir have been widely used to reduce the
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severity and duration of pain associated with acute neuritis; promote faster healing of cutaneous
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lesions; avoid formation of new lesions; decrease viral spread and reduce the risk of
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transmission; and avoid post-herpetic neuropathy.16,18 The assessment of intensity scores for

pain, vesicular lesions, loss of sensibility, burning pain and pruritus over the follow-up period
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showed no statistically significant difference between the two treatment groups.

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Safety profile of famciclovir has already been evaluated in immunocompetent patients with HZ,

using the incidence of adverse events and monitoring the outcome of laboratory variables.
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Saltzman et al. (1994) compiled safety data from 808 patients who received Famciclovir in three
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clinical studies with patients receiving Famciclovir for treatment of HZ or genital herpes and

demonstrated that this agent is well tolerated and has a safety profile comparable to that of
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placebo, favoring its use in the treatment of HZ, a disease in which treatment alternatives with

acceptable safety profiles are limited.19 In our study, safety assessment was performed by

assessing the incidence of adverse events in each of the groups, as well as the relationship of

these events to the medication used and severity of the reported events. During the follow-up
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period, there were 142 episodes of adverse events, 79 episodes (55.63%) in the Acyclovir group

and 63 episodes (44.37%) in the Famciclovir group, all of them non-serious and only 2 episodes

were not recovered (one in each group). Concerning adverse events, the main event was

headache, with 30 (21.12%) episodes in the Acyclovir group and 19 (13.38%) in the Famciclovir

group. Saltzman et al. (1994) reported similar headache rates in patients receiving Famciclovir

and those receiving placebo in 816 patients with HZ (4 studies), 409 patients with genital herpes

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virus infection (7 studies), and in 382 patients in two studies of genital herpes suppression. They

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also found no relationship between the duration of exposure to Famciclovir and the incidence

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of laboratory abnormalities.19 Similarly, our study demonstrated that 97.37% and 88% of the

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patients treated with Acyclovir and Famciclovir, respectively, did not present significant

alterations in the safety laboratory tests at both visits. In this way, the similarity of safety

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between the two treatments in relation to the laboratory tests is demonstrated.
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Nevertheless, the antiviral efficacy in terms of the proportion of patients with complete cure is
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as relevant as the time to complete cure. In this study we found results of efficacy, in terms of
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the proportion of patients with complete cure and time to complete healing, similar to that

presented in the literature. As a decision criterion to determine the non-inferiority of Famciclovir

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to Acyclovir in the treatment of HZ, a non-inferiority margin of 10% was established. Since the
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difference found was less than 10%, treatment with Famciclovir may be considered to be non-

inferior to Acyclovir.
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Conclusions

Treatment of HZ with antiviral agents has been shown to be effective in reducing or blocking
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viral replication, accelerating wound healing, limiting the severity and duration of acute pain and

other symptoms such as pruritus, loss of sensibility and burning pain, besides reducing the

complications. Therefore, the efficacy of Famciclovir 500 mg t.i.d. for 7 days as antiviral in
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patients with HZ emerges as an effective, convenient, well tolerated and safe alternative

comparable to the traditionally prescribed treatment, Acyclovir.

Conflict of Interest

H Pott-Junior has no conflict of interest to declare. MFB de Oliveira, S Gambero and RB

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Amazonas report receiving grants and consulting fees from EMS Industry.

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Ethical Approval

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We further confirm that any aspect of the work covered in this manuscript that has involved

either experimental animals or human patients has been conducted with the ethical approval

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of all relevant bodies and that such approvals are acknowledged within the manuscript.
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Acknowledgements
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The study was funded by EMS Pharma Inc., Hortolândia, SP, Brasil.
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References
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1. Pearce, J. Post herpetic neuralgia. J. Neurol. Neurosurg. Psychiatry 76, 572 (2005).

2. Thyregod, H. G. et al. Natural History of Pain Following Herpes Zoster. Pain 128, 148–156
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(2007).
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3. Sampathkumar, P., Drage, L. A. & Martin, D. P. Herpes zoster (shingles) and postherpetic
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neuralgia. Mayo Clin. Proc. 84, 274–280 (2009).

4. Cohen, J. I. Clinical practice: Herpes zoster. N. Engl. J. Med. 369, 255–263 (2013).
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5. Wilson, J. F. In the clinic. Herpes zoster. Ann. Intern. Med. 154, ITC31–15; quiz ITC316

(2011).

6. Dworkin, R. H. et al. Recommendations for the management of herpes zoster. Clin. Infect.

Dis. Off. Publ. Infect. Dis. Soc. Am. 44 Suppl 1, S1–26 (2007).
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7. Rodrigues, V., Gouveia, C. & Brito, M. J. Herpes Zoster na Infância. 138–140 (2010).

8. Shingles | Overview | Herpes Zoster | CDC. Centers for Disease Control and Prevention -CDC

Available at: https://www.cdc.gov/shingles/about/overview.html. (Accessed: 14th June

2017)

9. Dworkin, R. H. et al. Diagnosis and Assessment of Pain Associated With Herpes Zoster and

Postherpetic Neuralgia. J. Pain 9, 37–44 (2008).

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10. Johnson, R. W. et al. The impact of herpes zoster and post-herpetic neuralgia on quality-of-

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life. BMC Med. 8, 37 (2010).

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11. Reis, A. D., Pannuti, C. S. & de Souza, V. A. U. F. [Prevalence of varicella-zoster virus

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antibodies in young adults from different Brazilian climatic regions]. Rev. Soc. Bras. Med.

Trop. 36, 317–320 (2003).

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12. Sacks, S. L. & Wilson, B. Famciclovir/penciclovir. Adv. Exp. Med. Biol. 458, 135–147 (1999).
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13. Whitley, R. J. & Gnann, J. W. Acyclovir: a decade later. N. Engl. J. Med. 327, 782–789
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(1992).
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14. Degreef, H. & Famciclovir Herpes Zoster Clinical Study Group. Famciclovir, a new oral

antiherpes drug: results of the first controlled clinical study demonstrating its efficacy and
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safety in the treatment of uncomplicated herpes zoster in immunocompetent patients. Int.

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J. Antimicrob. Agents 4, 241–246 (1994).

15. Rampakakis, E. et al. Economic Burden of Herpes Zoster (‘culebrilla’) in Latin America. Int. J.
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Infect. Dis. IJID Off. Publ. Int. Soc. Infect. Dis. 58, 22–26 (2017).
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16. Hillebrand, K., Bricout, H., Schulze-Rath, R., Schink, T. & Garbe, E. Incidence of herpes

zoster and its complications in Germany, 2005-2009. J. Infect. 70, 178–186 (2015).
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17. Dworkin, R. H. et al. Recommendations for the management of herpes zoster. Clin. Infect.

Dis. Off. Publ. Infect. Dis. Soc. Am. 44 Suppl 1, S1–26 (2007).

18. Field, H. J. & Vere Hodge, R. A. Recent developments in anti-herpesvirus drugs. Br. Med.

Bull. 106, 213–249 (2013).

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19. Saltzman, R., Jurewicz, R. & Boon, R. Safety of famciclovir in patients with herpes zoster

and genital herpes. Antimicrob. Agents Chemother. 38, 2454–2457 (1994).

Figures

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Figure 1. Trial flowchart.

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Figure 2. Cox-Proportional Hazards Model. The cumulative hazard rate of time to full crusting of
the vesicular lesions captured over time (follow-up duration = 30 days) among treatment
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groups, sex, age and baseline pain score.

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Overall Famciclovir Acyclovir p-

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Variable
N=174 n=88 n = 86 value
Female, n (%) 113 (64.9) 60 (68.18) 55 (61,63) 0.428a
Age (years), mean ± sd 54.94 ± 17.28 55.90 ± 17.84 53.95 ± 16.75 0.460b
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Weight (kg), mean ± sd 73.98 ± 15.70 73.81 ± 16.02 74.16 ± 15,47 0.887b
Height (cm), mean ± sd 164.15 ± 9.86 163.59 ± 10.40 164.73 ± 9.29 0.449b
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Baseline evaluation (VAS, mm)

Pain, mean ± sd 6.16 ± 2.86 6.32 ± 2.81 5.99 ± 2.92 0.449b
Vesicular lesions, mean ± sd 6.43 ± 1.88 6.55 ± 2.09 6.31 ± 1.65 0.419b
Loss of sensibility, mean ± sd 3.59 ± 3.31 3.44 ± 3.27 3.74 ± 3.37 0.550b
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Burning pain, mean ± sd 6.26 ± 2.90 6.61 ± 1.97 5.90 ± 2.80 0.103b
Pruritus, mean ± sd 5.34 ± 3.45 5.41 ± 3.69 5.27 ± 3.21 0.788b
Abbreviation: sd = standard deviation; a = Fisher test; b = t-test.

Table 1. Descriptive statistics of demographic data and baseline visual analog scales for signs
and symptoms.

Acyclovir Famciclovir p-value Difference 95% CI

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N = 76 N = 75 Lower Upper
bound bound
Complete
72 (94.74) 71 (94.67) 0.985 0.07 -0.0718 0.0732
cure
Table 2. Efficacy analysis.

95% CI
Levene Difference
Treatment (n) Mean (SD) t-test Lower Upper
test
bound bound
Famciclovir (75) 3.84 (3.03)
Pain 0.643 0.707 -0.20 -1.22 0.83
Acyclovir (76) 3.64 (3.34)

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Famciclovir (75) 3.19 (2.33)
Vesicular lesions 0.458 0.522 -0.25 -1.03 0.53
Acyclovir (76) 2.93 (2.51)

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Day Famciclovir (75) 1.25 (2.63)
Loss of sensibility 0.060 1.83 0.60 -0.29 1.49
7 Acyclovir (76) 1.86 (2.89)

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Famciclovir (75) 4.40 (3.28)
Burning 0.471 0.283 -0.60 -1.69 0.50
Acyclovir (76) 3.80 (3.52)

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Famciclovir (75) 2.85 (3.51)
Pruritus 0.644 0.635 -029 -1.48 0.91
Acyclovir (76) 2.57 (3.91)
Pain Famciclovir (75) 4.99 (2.85)
0.986 0.580 -0.25 -1.16 0.65

Vesicular lesions
Acyclovir (75)
Famciclovir (75)
4.73 (2.75)
4.81 (2.49) U
0.079 0.885 0.05 -0.67 0.78
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Acyclovir (75) 4.87 (1.98)
Day Loss of sensibility Famciclovir (75) 2.19 (2.89)
0.050 0.242 0.59 -0.40 1.57
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15 Acyclovir (75) 2.77 (3.22)
Burning Famciclovir (75) 5.36 (3.29)
0.587 0.703 -0.20 -1.23 0.83
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Acyclovir (75) 5.16 (3.12)

Pruritus Famciclovir (75) 3.73 (4.09)
0.095 0.741 0.21 -1.06 1.49
Acyclovir (75) 3.95 (3.80)
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Pain Famciclovir (76) 5.59 (2.87)

0.769 0.738 -0.16 -1.10 0.78
Acyclovir (74) 5.43 (2.98)
Vesicular lesions Famciclovir (76) 6.19 (2.29)
0.009 0.363 -0.29 -093 0.34
Acyclovir (74) 5.89 (1.61)
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Day Loss of sensibility Famciclovir (76) 2.78 (3.15)

0.413 0.277 0.57 -0.46 1.61
28 Acyclovir (74) 3.36 (3.26)
Burning Famciclovir (76) 6.16 (3.15)
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0.904 0.348 -0.48 -1.48 0.52

Acyclovir (74) 5.68 (3.06)
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Pruritus Famciclovir (76) 4.49 (4.22)

0.044 0.867 0.11 -1.14 1.35
Acyclovir (74) 4.59 (3.46)
Abbreviation: SD = standard deviation.

Table 3. VAS score evolution of signs/ symptoms in 7, 15 and 28 days after starting treatment.
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