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Diaz-Mitoma F, Sibbald RG, Shafran SD, Boon R, Saltzman RL, for the Collaborative Famciclovir Genital Herpes Research Group. Oral Famciclovir for the Suppression of Recurrent Genital Herpes: A Randomized Controlled Trial. JAMA. 1998;280(10):887–892. doi:10.1001/jama.280.10.887
From the Children's Hospital of Eastern Ontario, Ottawa (Dr Diaz-Mitoma), and the Women's College Hospital, Toronto, Ontario (Dr Sibbald); the Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton (Dr Shafran); SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Harlow, England (Mr Boon); and SmithKline Beecham Pharmaceuticals, King of Prussia, Pa (Dr Saltzman).
Context.— Recurrent genital herpes simplex virus (HSV) may be treated episodically,
but this may not be sufficient for patients with frequent recurrences.
Objective.— To determine the efficacy and safety of famciclovir in the suppression
of recurrent genital HSV infection.
Design.— A randomized, double-blind, placebo-controlled, parallel-group study.
Setting.— Thirty university, hospital, or private outpatient referral centers
in Canada and Europe.
Patients.— A total of 455 patients (223 men, 232 women) aged 18 years or older
with a history of 6 or more episodes of genital herpes during 12 of the most
recent 24 months, in the absence of suppressive therapy, received study medication.
Intervention.— Oral famciclovir, 125 mg or 250 mg 3 times daily or 250 mg twice daily,
or placebo for 52 weeks.
Main Outcome Measures.— Time to the first recurrence of genital HSV infection; the proportion
of patients remaining free of HSV recurrence at 6 months; frequency of adverse
Results.— In an intent-to-treat analysis, famciclovir significantly delayed the
time to the first recurrence of genital herpes at all dose regimens (hazard
ratios, 2.9-3.3;P< .001); median time to recurrence
for famciclovir recipients was 222 to 336 days compared with 47 days for placebo
recipients. The proportion of patients remaining free of HSV recurrence was
approximately 3 times higher in famciclovir recipients (79%-86%) than in placebo
recipients (27%) at 6 months (relative risks, 2.9-3.1;P <.001); efficacy was maintained at 12 months. Famciclovir was well
tolerated with an adverse experience profile comparable to placebo.
Conclusions.— Oral famciclovir (125 mg or 250 mg 3 times daily or 250 mg twice daily)
is an effective, well-tolerated treatment for the suppression of genital HSV
infection in patients with frequent recurrences.
GENITAL HERPES simplex virus (HSV) infection is one of the most common
sexually transmitted diseases. Serologic studies using Western blot have demonstrated
HSV-2 prevalence of approximately 22% in adults in the United States, 7% to
28% among different populations in Europe, and 20% to 40% in selected countries
in Africa.1-3 Symptomatic
recurrent infection occurs in the majority of patients who develop symptomatic
primary HSV-2 infection, with almost half of these patients experiencing at
least 6 recurrences annually.4 Recurrent lesions
may be painful or pruritic and the psychological consequences of the disease,
particularly the fear of transmitting the virus to others, may be severe and
Recurrent genital herpes can be successfully managed with episodic antiviral
treatment in many patients. Acyclovir has been available for a number of years,
and more recently, valacyclovir hydrochloride and famciclovir have been approved
for use in the acute treatment of recurrent genital herpes. However, for patients
with frequent symptomatic recurrences, such management may not be considered
sufficient, and preventive treatment to suppress recurrences may provide more
benefit than acute treatment.5-7
Famciclovir is the oral form of penciclovir, a novel nucleoside analog
that shares the same antiviral spectrum as acyclovir for herpesviruses and
has similar potency and selectivity. The oral bioavailability of penciclovir
is 77% following administration of famciclovir,8
significantly higher than the bioavailability of acyclovir (10%-20%).9 The intracellular half-life of penciclovir triphosphate
is significantly longer than that of acyclovir triphosphate in HSV-infected
cells in vitro (10-20 hours for penciclovir triphosphate compared with ≤1
hour for acyclovir triphosphate).10 Placebo-controlled
studies of famciclovir in the acute treatment of recurrent genital herpes
have demonstrated unequivocal evidence for efficacy on virological lesion
healing and symptom parameters.11,12
The efficacy of famciclovir in the suppression of recurrent genital
herpes was investigated in a preliminary, placebo-controlled, dose-ranging
study in women with frequent recurrences.13
Patients were treated for 4 months with oral famciclovir, 125 mg once daily
or twice daily, 250 mg once daily or twice daily, or 500 mg once daily, or
with placebo. Results from this study indicated that 250 mg given twice daily
for 4 months was an effective, well-tolerated treatment for the suppression
of genital herpes, with 90% of patients remaining free of HSV recurrence for
the duration of the study. Once-daily dosing with famciclovir produced less
complete suppression with approximately 60% to 70% of patients remaining free
of HSV recurrences. These data are consistent with the results of a dose-ranging
study of suppressive oral acyclovir that suggests that twice-daily or 3-times-daily
regimens may be more effective than once-daily treatment using equal or higher
cumulative daily doses.14
The favorable biological properties of penciclovir and famciclovir and
the results of this dose-ranging study to evaluate suppression highlight the
potential therapeutic value of famciclovir in the suppression of recurrent
genital herpes. The current multicenter, double-blind, randomized, placebo-controlled
trial therefore was conducted to determine the efficacy and safety of famciclovir
at doses of 250 mg twice daily, 125 mg or 250 mg 3 times daily in the suppression
of recurrent genital herpes. Although a high degree of efficacy was established
for the 250-mg twice-daily regimen of famciclovir in the preliminary dose-ranging
suppression study,13 a minority of patients
still experienced HSV recurrences. To explore whether the efficacy of famciclovir
could be further improved, the 3-times-daily regimens were incorporated into
the design of this study.
The study was conducted at 30 university, hospital, or private referral
centers located in Belgium (2 sites), Canada (9 sites), France (12 sites),
Iceland (1 site), Sweden (1 site), and the United Kingdom (5 sites). The protocol
and statement of informed consent were approved by an institutional review
board (or ethics committee) prior to each center's initiation.
Otherwise healthy male or female patients, aged 18 years or older, with
a history of recurrent genital herpes, confirmed by serology, culture, or
both, were eligible for inclusion. Written informed consent was obtained from
each patient prior to entry into the study.
Patients who had not been treated with suppressive acyclovir in the
year prior to study entry were eligible for inclusion if they had experienced
6 or more recurrences in the preceding 12 months. Patients who had been treated
with suppressive acyclovir in the preceding 12 months were eligible if they
had a history of 6 or more episodes during any 12-month period in the 2 years
prior to study entry while not receiving suppressive acyclovir.
Patients were excluded if they were pregnant or breast-feeding, were
immunocompromised, or had received antiviral therapy during the previous 14
The study was double blind and placebo controlled. Eligible patients
were sequentially allocated a unique patient number at each center according
to a computer-generated randomization code; the patient number determined
the assignment to 1 of 3 famciclovir regimens (125 mg 3 times daily, 250 mg
twice daily, or 250 mg 3 times daily) or to placebo. Tablets
containing placebo were identical to those containing each dosage of famciclovir,
and there were no reports of compromised blinding by vision or taste. The
study medication was blister packed, and packs were labeled with the patient
number. To maintain the study blind, patients were instructed to take tablets
4 times daily at the times indicated on the blister packs (0700, 1500, 1900,
and 2300). Patients randomized to the twice-daily regimen (every 12 hours)
received placebo tablets only at 1500 and 2300; patients randomized to the
3-times-daily regimens (every 8 hours) received only placebo tablets at 1900.
Patients took 7 tablets daily during each regimen.
The patient, the investigator, and the sponsor personnel directly involved
in monitoring the study or reviewing the data had no knowledge of what treatment
had been allocated until the code was unblinded and the data were analyzed.
The medication code for a particular patient was only to be broken in the
event of a serious adverse experience that the investigator felt could not
be adequately treated without knowing the identity of the study medication;
the treatment blind was kept intact and was not broken for any patient during
Patients were requested to take tablets each day at the times and in
the sequence presented on blister packs. Treatment continued for 52 weeks.
Patients were required to attend the clinic for a scheduled visit every
28 days. If the patient suspected a lesional episode, he or she was required
to return to the clinic within 24 hours of the start of the recurrence for
confirmation of the episode.
Patients were encouraged to continue in the study despite recurrences
of genital herpes. However, after patients had experienced either 2 virologically
confirmed or 3 clinically confirmed recurrences, they were given the option
of receiving open-label famciclovir (250 mg 3 times daily) for the remainder
of the 52 weeks of the study.
Data for the analysis of both primary and secondary efficacy parameters
were provided from investigator assessments of lesional episodes, patient
self-assessment of episodes (using a diary card), and viral culture of lesions
during recurrences. Isolation of HSV was performed at laboratories local to
the research sites using standard cell-culture isolation procedures.
Adverse experiences were identified by the investigator or elicited
from the patient in response to the question, "Have you felt different in
any way since starting the treatment or since your last assessment?"
Because patients who were experiencing confirmed recurrences were given
the option of withdrawing from the double-blind phase of the study and receiving
open-label famciclovir, the period for safety monitoring for placebo recipients
was considerably shorter than that for famciclovir recipients (mean duration
of exposure ranged from 277 to 287 days for famciclovir recipients compared
with 170 days for placebo recipients). The number of adverse events reported
correlated with the length of time that a patient participated in the double-blind
phase of the study. Thus, to compare the incidences of adverse events between
famciclovir and placebo groups in a consistent and unbiased fashion, data
from those patients receiving long-term suppressive therapy (≥10 months
of double-blind study medication) have been summarized.
At each visit, blood samples were taken for measurement of hematologic
and clinical chemistry parameters; urinalysis was also performed.
A sample size of 73 patients per treatment group was required to detect
a 30% difference compared with placebo in the proportion of patients who remained
free of HSV recurrence for at least 6 months. This assumed at least 90% power
and testing at the 1.67% significance level (using the Bonferroni adjustment15 to ensure that the type I error did not exceed 5%).
With 73 patients per group, the study also had 90% power to detect a ratio
of 1:1.85 for the median time to the first recurrence following the start
of study medication.
A target enrollment of approximately 120 patients per group was set
to provide 73 patients per group with evaluable data.
Statistical analyses were based on data recorded during double-blind
treatment only. All analyses were performed on an intent-to-treat population
(ie, those patients who were randomized to and received at least 1 dose of
study medication). Statistical tests were 2 sided, and 3 pairwise comparisons
(ie, each active group vs placebo) were made.
The primary efficacy parameters were the time to the first recurrence
after the start of study medication and the proportions of patients who remained
free of HSV recurrences (culture confirmed) for at least 6 months after the
start of study medication. The proportions of patients who remained free of
HSV recurrences for at least 12 months after the start of study medication
were evaluated as a secondary efficacy parameter. In addition, the median
number of recurrences per year was evaluated.
The times to first recurrence were analyzed using the Cox proportional
hazards regression model stratified by center; 95% confidence intervals for
the hazard ratio (famciclovir:placebo) and median times were also presented.
The comparisons of the proportions of patients free of HSV recurrence were
summarized by relative risks (famciclovir:placebo) and analyzed using the
Cochran-Mantel-Haenszel test stratified by center. The median numbers of recurrences
were expressed as yearly recurrence rates and analyzed using the Wilcoxon
rank sum test, stratifying by investigational center.
All patients who received at least 1 dose of double-blind study medication
were included in the analyses of time to first event and frequency of events.
Recurrence-free proportions were based on the population known either to have
experienced at least 1 recurrence or to have been recurrence free during the
entire reference time interval.
Clinical laboratory results were evaluated by calculating mean differences
from baseline and by identifying laboratory values of potential clinical concern
(values that had changed from baseline by more than a specified amount and
were outside the sponsor-defined extended normal range).
A total of 457 patients were randomized to the study (Figure 1); 2 patients did not take any study medication; thus, the
455 patients who received double-blind study medication constituted the intent-to-treat
population. A total of 223 patients were male (42%-55% in each treatment group),
and the mean age ranged from 35 to 38 years (Table 1).
Between 92% and 96% of patients in each group had documented laboratory
confirmation of their recurrent genital herpes at enrollment; between 69%
and 77% of patients had their infection confirmed by culture and between 22%
and 28% by serology. The mean duration of genital herpes was approximately
7 years, and 405 (85%) of the 455 patients had experienced at least 10 recurrences
in the 2 years prior to study entry. Sixty-eight patients (15%) had received
suppressive therapy with acyclovir in the previous 12 months, and 177 patients
(40%) had received episodic acyclovir treatment.
A total of 218 patients withdrew from the study while receiving double-blind
medication (Figure 1). The withdrawal
rate for placebo recipients (88 [77%] of 114) was approximately double the
rate overall for famciclovir recipients (130 [38%] of 341). Furthermore, the
proportion of patients withdrawing due to lack of efficacy in the placebo
group (63 [55%] of 114) was approximately 3-fold higher than the proportion
in the famciclovir groups (56 [16%] of 341). The proportions of patients who
withdrew while still free of HSV recurrence were similar in each treatment
group (22%-31% in the famciclovir groups, 23% in the placebo group). Other
reasons for withdrawal included adverse events, lack of compliance, protocol
violations, and loss to follow-up (Figure
The majority of patients (more than 92% in each treatment group) were
compliant (≥80% of patients) with double-blind medication.
The time to the first recurrence (Table 2) was significantly prolonged for patients who received famciclovir
(hazard ratios, 2.9-3.3; P<.001). The median time
to the first recurrence was more than 7 months for the lowest-dose regimen
of famciclovir (125 mg 3 times daily) and more than 10 months for the famciclovir
250 mg twice-daily or 250 mg 3-times-daily regimens compared with approximately
7 weeks for placebo recipients.
The proportion of patients remaining free of HSV recurrence was significantly
higher for famciclovir recipients (Figure
2), with approximately 3 times more famciclovir recipients (125
mg 3 times daily, 69 [81%] of 85; 250 mg twice daily, 81 [79%] of 102; 250
mg 3 times daily, 74 [86%] of 86) than placebo recipients (25 [27%] of 91)
remaining free of HSV recurrences at 6 months (relative risk, 2.9-3.1; P<.001). This difference was maintained at 12 months;
again, approximately 3 times more famciclovir recipients (125 mg 3 times daily,
55 [71%] of 77; 250 mg twice daily, 65 [72%] of 90; 250 mg 3 times daily,
65 [80%] of 81) than placebo recipients (19 [22%] of 88) remained free of
HSV recurrences (relative risk, 3.3-3.6; P<.001).
The median number of patient-reported recurrences per year ranged from
1 to 1.8 episodes for famciclovir recipients compared with 5.1 episodes for
placebo recipients. The median number of investigator-reported recurrences
per year ranged from 0 to 1.0 episode for famciclovir recipients compared
with 4.4 episodes for placebo recipients (Table 3). These differences were statistically significant for all
3 famciclovir groups (P<.001).
For both of the primary efficacy variables, the 3 famciclovir regimens
were comparable; treatment with famciclovir, 250 mg twice daily, 125 mg 3
times daily, and 250 mg 3 times daily had similar efficacy. There was no difference
in efficacy for either male or female patients (data not shown).
Adverse Experiences. Famciclovir was well tolerated during both the double-blind and open-label
phases of the study, with an adverse experience profile that was comparable
with placebo. The most common events occurring in the double-blind phase for
patients receiving either famciclovir or placebo for at least 10 months were
headache, viral infection (influenza, flulike symptoms, cold symptoms), and
upper respiratory tract infection (Table
Only 20 patients had adverse experiences classified as "serious" during
double-blind treatment: 5 (4.5%), 3 (2.6%), and 7 (6.2%) in the famciclovir,
125 mg 3 times daily, 250 mg twice daily, and 250 mg 3 times daily, groups,
respectively, and 5 (4.4%) in the placebo group. Only 2 patients experienced
serious events that were considered by the investigator to be possibly related
to study medication, and no patients experienced serious events considered
to be related to study medication. The serious events considered to be possibly
related were as follows: 1 patient in the famciclovir, 125 mg 3 times daily,
group had elevated levels of bilirubin and lipase after 10 months of treatment,
which resolved on therapy after 7 days and remained normal for the rest of
the study; 1 patient in the placebo group developed severely increased amylase
and lipase levels after approximately 3 weeks of treatment (clinical pancreatitis
was not reported); study medication (placebo) was withdrawn, and the increased
enzyme levels resolved 6 days later.
Laboratory Tests. While there were isolated differences in laboratory parameters between
treatment groups, no consistent pattern or dose response could be identified.
In general, the incidence of laboratory abnormalities was comparable between
the 3 famciclovir groups and the placebo group.
The objective of this study was to evaluate clearly the efficacy and
safety of oral famciclovir in the suppression of recurrent genital herpes.
In many patients, recurrent genital herpes can be successfully managed with
episodic treatment; however, such management may not be considered sufficient
for patients with frequent symptomatic recurrences. To illustrate this, when
patients with a history of 6 or more episodes of genital herpes per year were
offered a choice of either suppressive or episodic therapy after completing
a 1-year study with acyclovir, 89% of patients opted for suppressive therapy.5
The results from the current study clearly demonstrate yearlong treatment
with famciclovir to be effective in the suppression of lesional episodes of
genital herpes at all 3 dose regimens examined (125 mg 3 times daily, 250
mg twice daily, and 250 mg 3 times daily). The time to the first genital herpes
outbreak was approximately 3 times longer for famciclovir recipients than
for placebo recipients (hazard ratios, 2.9-3.3; P<.001);
the time differences generally equate to approximately 9 months' delay compared
with placebo. Similarly, approximately 80% of famciclovir recipients remained
free of HSV recurrences at 6 months compared with only 27% of placebo recipients.
This difference was sustained at 12 months with approximately 75% of famciclovir
recipients remaining free of HSV recurrences compared with only 22% of placebo
recipients. In addition, famciclovir-treated patients experienced approximately
80% fewer recurrences per year than placebo recipients.
It is not appropriate to make direct comparisons between the results
obtained in our study and those obtained in trials of suppressive acyclovir
that were initiated before the licensure of oral acyclovir and widespread
use of suppressive therapy; the patient populations involved in these studies
are likely to be different. Nevertheless, studies have demonstrated that acyclovir,
at a dose of 400 mg twice daily or 200 mg 3 to 5 times daily, is effective
and safe when used as suppressive therapy for recurrent genital herpes for
up to 10 years in immunocompetent patients.5,6,13,16-22
In 1-year studies, approximately 45% of patients receiving acyclovir at a
dose of 400 mg twice daily remained recurrence free for 12 months compared
with fewer than 10% of placebo recipients.19,22
Acyclovir recipients experienced a marked decrease in the number of recurrences
per year, with no emergence of toxic effects over time.6
No significant changes in resistance patterns in acyclovir recipients
have been detected even after long-term suppressive therapy; the prevalence
of acyclovir-resistant HSV isolates in immunocompetent patients is low (typically
around 0.3% of isolates).23 Similarly, no resistant
virus was detected in any virus isolates obtained from famciclovir-treated
patients in the current study; 1 resistant isolate was isolated from a patient
receiving placebo. To date, no treatment-related HSV resistance has been detected
in virus isolates from any clinical trial with famciclovir or penciclovir
(R. Sarisky, MD, SmithKline Beecham, oral communication, May 25, 1998).
Famciclovir, 250 mg given twice daily, was found to be of similar efficacy
to 3-times-daily regimens of famciclovir and provides convenience advantages
that are particularly important for the long-term management of recurrent
genital herpes. It has previously been demonstrated in women that the same
total daily dose of famciclovir (500 mg) given once daily was clearly less
effective than a twice-daily regimen.13 These
data are consistent with the results of a dose-ranging study that investigated
a number of different doses and dosing frequencies of suppressive oral acyclovir
therapy, which suggest that twice-daily or 3-times-daily regimens of acyclovir
may be more effective than once-daily treatment using equal or higher cumulative
daily doses.14 To further support this, recent
data with valacyclovir have also shown that a twice-daily regimen was more
effective than a once-daily regimen in the suppression of frequently recurring
All regimens of famciclovir were well tolerated. No differences were
observed in the frequency and severity of clinical adverse experiences between
famciclovir and placebo recipients, and no evidence was seen of hematologic,
renal, or hepatotoxic effects in any of the famciclovir groups. The safety
of oral famciclovir has already been established for the acute treatment of
genital herpes infections,11,12
and our study confirms that long-term treatment with famciclovir is well tolerated
with a safety profile comparable with placebo.
In summary, famciclovir at a dose of 250 mg twice daily provides a convenient,
effective, and well-tolerated regimen for patients with recurrent genital
herpes. Patients receiving famciclovir at a dose of 250 mg twice daily remained
free of HSV recurrence for a median of 11 months and reported 80% fewer recurrences
per year when compared with placebo recipients. For patients with frequent
recurrences, suppressive therapy with famciclovir provides a potent and effective
therapy, enabling patients to remain free from pain and discomfort and to
regain a better quality of life.
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