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Clayton Research Institute, St. Louis, Missouri; Departments of 2Dermatology, 3Microbiology and Molecular Genetics, and 4Internal Medicine,
University of Texas Health Science Center, Houston; 5Medical Center for Clinical Research, San Diego, California; 6Novartis, East Hanover,
New Jersey; and 7Taylor Square Private Clinic, Darlinghurst, New South Wales, Australia
Background. Recurrent genital herpes is a major problem for patients worldwide. Early episodic treatment
with short-course therapy is effective, often stopping progression of outbreaks. This study is the first head-to-head
comparison of single-day famciclovir (1000 mg administered twice daily) versus 3-day valacyclovir (500 mg
administered twice daily) for episodic therapy in immunocompetent patients.
Methods. In this multicenter, multinational, double-blind, parallel-group study, 1179 adults with a history of
recurrent genital herpes were randomized 1:1 to receive either famciclovir or valacyclovir. Patients initiated treatment within 6 h after a recurrence. The primary objective was to establish noninferiority of single-day famciclovir,
compared with a 3-day course of valacyclovir, in time to healing of all nonaborted lesions in a modified intentto-treat population.
Results. This study established that single-day famciclovir therapy was noninferior to 3-day valacyclovir therapy
in reducing time to healing of all nonaborted genital herpes lesions (median time to healing, 4.25 days vs. 4.08
days). Approximately one-third of patients in each treatment group had aborted genital herpes episodes, suggesting
that both treatments have similar efficacy in preventing outbreaks or progression of lesions beyond the papule
stage. There was no significant difference in time to resolution of symptoms associated with recurrence. The overall
incidence of adverse events was similar (23.2% for the famciclovir group vs. 22.3% for the valacyclovir group),
with headache, nausea, diarrhea, vomiting, and abdominal pain reported most often.
Conclusions. Single-day famciclovir (1000 mg administered twice daily) was similar to 3-day valacyclovir (500
mg administered twice daily) in both efficacy and safety, representing a more convenient treatment for immunocompetent adults with recurrent genital herpes.
Genital herpes is a sexually transmitted disease most
commonly caused by herpes simplex virus type 2 (HSV2), although infection due to type 1 (HSV-1) has been
increasingly implicated as oral-genital sexual behavior
has increased [1, 2]. Approximately 17% of adults in
the United States are seropositive for HSV-2 [3], with
prevalence rates approaching 30% worldwide [4]. The
or severe), relationship to study drug (suspected or not suspected), and whether the AE resulted in discontinuation of
study medication or other remedial action. Serious AEs were
defined as AEs that were fatal, life threatening, or disabling;
that resulted in hospitalization; or that required medical or
surgical intervention to prevent one of these outcomes.
Analysis populations. The safety population included all
patients who had initiated treatment with the study drug and
had at least 1 postbaseline safety assessment. All patients who
initiated treatment using study medication with the intention
of treating genital herpes recurrences were included in the intent-to-treat (ITT) population. A modified ITT population
the primary efficacy populationincluded all patients who developed nonaborted genital herpes lesions during the treated
recurrence. The per-protocol (PP) population included all patients from the modified ITT population who did not have
major protocol deviations (e.g., noncompliance with study drug
treatment).
Statistical analysis. The primary efficacy end point was
investigator-assessed time to healing of all nonaborted genital
herpes lesions. Secondary end points included the proportion
of patients with investigator-assessed aborted lesions, investigator-assessed time to healing of all genital herpes lesions (nonaborted and aborted), and patient-reported time to resolution
of all genital herpesassociated symptoms and specific genital
herpesassociated symptoms.
Sample size calculations were based on the following assumptions: median time to healing of 4.5 days for both treatment groups, with the distribution of time to healing similar
to that from a previous study [12], a censoring rate of 10%,
and a noninferiority margin of 1.0 day. A total of 260 patients
with nonaborted lesions (including dropouts) in each treatment
group was required to have 90% power for establishing noninferiority. The sample size was estimated using SAS and
StatXact Procs for SAS simulations (SAS).
The primary analysis was performed for the time to healing
of nonaborted lesions for the modified ITT population and
presented as the 2-sided Hodges-Lehman 95% CI of the median
of the treatment difference (famciclovir minus valacyclovir).
The noninferiority of single-day famciclovir compared with the
3-day valacyclovir regimen was confirmed if the upper bound
of the 95% CI was less than the predefined noninferiority margin of 1.0 day. To assess the robustness of the primary analysis
result, a similar 95% CI was constructed for the PP population
and the modified ITT population without missing values. The
primary efficacy end point and other secondary time-to-event
variables were analyzed using a proportional hazards model,
with treatment, sex, and study center as explanatory variables;
hazard ratios (famciclovir:valacyclovir) were estimated, and
their 95% CIs were constructed; and the Kaplan-Meier method
was used to present distributions. The proportion of patients
with aborted lesions was compared between treatment groups
using the Cochran-Mantel-Haenszel test, stratified by sex and
study center. All hypothesis tests were performed as planned
and evaluated at a .05 level of statistical significance. No adjustments for multiplicity were performed for secondary analyses. Rates of AEs and laboratory test abnormalities were summarized descriptively.
RESULTS
Patient disposition. Of 1179 randomized patients, 756 received at least 1 dose of study medication (the safety population), and 751 comprised the ITT population. A total of 5
Table 1. Demographic and baseline medical characteristics of the intent-to-treat population in a trial
comparing single-day famciclovir therapy with 3-day valacyclovir therapy for recurrent genital herpes.
Characteristic
Famciclovir
(n p 370)
Valacyclovir
(n p 381)
39 (1873)
245 (66.2)
41 (1885)
243 (63.8)
260 (70.3)
253 (66.4)
94 (25.4)
7 (035)
111 (29.1)
8 (048)
6 (340)
262 (70.8)
5 (420)
275 (72.2)
72 (19.5)
67 (17.6)
Race
White
Black
Median no. of years in which patient experienced recurrent genital herpes (range)
Median no. of genital herpes recurrences during previous 12 months or in the 12
months immediately preceding suppressive treatment (range)
Received episodic antiherpes therapy
Received suppressive antiherpes therapy in previous 12 months
Herpes simplex virus serotype
Type 1 only
32 (8.6)
26 (6.8)
Type 2 only
165 (44.6)
186 (48.8)
173 (46.8)
169 (44.4)
Table 2. Time to healing of lesions for famciclovir and valacyclovir recipients with recurrent genital herpes.
No. of
patients
Efficacy parameter
Median days to
Median days of difference in time to
healing of lesions,
healing between treatments
a
b
Hazard ratio (95% CI)
by Kaplan-Meier method
(95% CI)
Nonaborted lesions
c
249
4.25
Valacyclovir group
253
4.08
1.08 (0.881.32)
.48
ND
ND
1.09 (0.871.37)
.44
0.00 (0.000.00)
1.07 (0.911.25)
.42
218
4.07
Valacyclovir group
230
4.02
PP population
Famciclovir group
182
4.45
Valacyclovir group
196
4.14
Famciclovir group
370
3.07
Valacyclovir group
381
3.01
ITT population
Median of difference between treatments (famciclovir minus valacyclovir) was estimated using Hodges-Lehman shift model.
Hazard ratio and P value were based on Cox proportional hazards model with treatment, pooled center, and sex as exploratory variables.
c
For patients with nonaborted lesions who discontinued the study before healing of nonaborted lesions was confirmed and for patients who completed the
study at 21 days after treatment initiation without nonaborted lesions and without a final assessment of aborted lesion status, the time to healing was censored
at the time of the last clinical lesion observation for the Kaplan-Meier estimation and Cox model; for Hodges-Lehman estimation, the missing data for time to
healing were imputed using the larger value of either the maximum value of time to healing observed in the study plus 1 day or time to censoring plus 2 days.
d
Patients with missing data for time to healing were excluded.
e
Patients with aborted lesions were assigned a time to healing of 0 days.
b
Figure 1. Kaplan-Meier plot of time to healing of all nonaborted genital herpes lesions (modified intent-to-treat population)
Table 3. Time to resolution of symptoms associated with recurrent genital herpes lesions (intent-to-treat
population).
No. of patients
whose symptom(s)
resolved (uncensored data)
Median hours to
resolution
a
(interquartile range)
Famciclovir group
Valacyclovir group
Pain
236
238
Famciclovir group
Valacyclovir group
Symptom
72.9 (47.8137.4)
72.0 (46.2131.9)
1.03 (0.861.24)
.75
182
177
18.0 (0.052.7)
20.1 (0.046.2)
1.00 (0.851.17)
.96
1.02 (0.861.20)
.84
All symptoms
Itching
Famciclovir group
229
43.9 (12.276.7)
Valacyclovir group
Tingling
209
42.3 (11.585.3)
Famciclovir group
Valacyclovir group
217
226
23.8 (0.058.0)
23.0 (0.050.5)
1.13 (0.961.33)
.13
Famciclovir group
176
16.1 (0.050.5)
1.08 (0.921.26)
.35
Valacyclovir group
Tenderness
Famciclovir group
Valacyclovir group
179
12.6 (0.047.5)
210
223
55.2 (20.4106.0)
47.9 (14.387.3)
1.06 (0.901.26)
.47
Burning
The Kaplan-Meier method was used to estimate the time to resolution at quartiles. Median time to resolution of all symptoms
and individual symptoms was estimated using both uncensored and censored data. Uncensored data were obtained from 474
patients who reported at least 1 symptom after initiation of treatment and had a known resolution time for all symptoms (i.e.,
actual time of resolution was recorded) and 7 patients who reported no symptoms (i.e., time of resolution was set as 0 h).
Censored data were obtained from 241 patients with at least 1 persistent symptom (i.e., time of resolution was set as the
last valid entry after first dose) and 29 patients with no valid data available (i.e., time of resolution was set as 0 h).
b
Based on Cox proportional hazards model with treatment, pooled center, and sex as explanatory variables. Hazard ratio
for time to healing was defined as the hazard rate of famciclovir group/hazard rate of valacyclovir group.
virus early and hard, when viral titers are highest [16], may
be responsible for the effectiveness of single-day high-dose famciclovir and the fact that, in approximately one-third of patients, the outbreak did not progress beyond the papule stage.
The present study demonstrated that single-day high-dose
famciclovir therapy was safe and well tolerated (overall AE rates,
23.2% for famciclovir vs. 22.3% for valacyclovir), with gastrointestinal and nervous system disorders reported most commonly. The majority of AEs were of mild-to-moderate severity,
with little need for remedial treatment. Only 1 famciclovirtreated patient discontinued medication prematurely, after experiencing headache and nausea. These findings, coupled with
earlier observations [12], suggest that single-day famciclovir has
an acceptable tolerability profile.
In summary, this multicenter, multinational, double-blind,
active-controlled study demonstrated that a patient-initiated
single-day famciclovir regimen (1000 mg administered twice)
was as effective and safe as a 3-day valacyclovir regimen (500
mg administered twice daily) in reducing the time to healing
of nonaborted lesions in immunocompetent adults with recurrent genital herpes. The fact that nearly one-third of patients
who were treated with single-day high-dose famciclovir had
aborted episodes is encouraging and demonstrates that effective
short-course therapy can significantly reduce the undesirable
sequelae associated with recurrences. Single-day famciclovir is
a simple and convenient treatment regimen for adults with
recurrent genital herpes.
Acknowledgments
We thank the volunteers for their participation in this study.
Financial support. Novartis.
Potential conflicts of interest. Famciclovir is manufactured by Novarits
under the brand name Famvir. M.A. has received research funding and
speakers honoraria from Novartis. S.T. has received research funding and
speakers honoraria from Novartis and GlaxoSmithKline. W.K. has received
research funding and speakers honoraria from Novartis, Bayer, Biosante,
Boehringer Ingelheim, Duramed, Dynogen, GlaxoSmithKline, Kanion,
Merck, Neurocrine Biosciences, Nventa, Pharm-Olam International, Proctor and Gamble, Roche, Sanofi Aventis, Shionog, Tap Pharmaceuticals,
Upsher Smith, Warner Chilcott, Wyeth, Xanodyne Pharmaceuticals, and
3M. N.B. has been a consultant for and has received research funding from
Novartis and GlaxoSmithKline. K.H. is an employee of Novartis.
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