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Long-term Effectiveness of Treatment With Terbinafine vs Itraconazole in Onychomycosis
A 5-Year Blinded Prospective Follow-up Study
Bárður Sigurgeirsson, MD, PhD;
Jón H. Ólafsson, MD, PhD;
Jón þ Steinsson, MD;
Carle Paul, MD;
Stephan Billstein, MD;
E. Glyn V. Evans, MD
Arch Dermatol. 2002;138:353-357.
ABSTRACT
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Objective To examine long-term cure and relapse rates after treatment with continuous
terbinafine and intermittent itraconazole in onychomycosis.
Design Long-term prospective follow-up study.
Setting Three centers in Iceland.
Subjects The study population comprised 151 patients aged 18 to 75 years with
a clinical and mycological diagnosis of dermatophyte toenail onychomycosis.
Interventions In a double-blind, double-dummy study, patients were randomized to receive
either terbinafine (250 mg/d) for 12 or 16 weeks or itraconazole (400 mg/d)
for 1 week in every 4 for 12 or 16 weeks (first intervention). Patients who
did not achieve clinical cure at month 18 or experienced relapse or reinfection
were offered an additional course of terbinafine (second intervention).
Main Outcome Measures The primary efficacy criterion was mycological cure, defined as negative
results on microscopy and culture at the end of follow-up and no requirement
of second intervention treatment. Secondary efficacy criteria included clinical
cure without second intervention treatment and mycological and clinical relapse
rates.
Results Median duration of follow-up was 54 months. At the end of the study,
mycological cure without second intervention treatment was found in 34 (46%)
of the 74 terbinafine-treated subjects and 10 (13%) of the 77 itraconazole-treated
subjects (P<.001). Mycological and clinical relapse
rates were significantly higher in itraconazole vs terbinafine-treated patients
(53% vs 23% and 48% vs 21%, respectively). Of the 72 patients who received
subsequent terbinafine treatment, 63 (88%) achieved mycological cure and 55
(76%) achieved clinical cure.
Conclusion In the treatment of onychomycosis, continuous terbinafine provided superior
long-term mycological and clinical efficacy and lower rates of mycological
and clinical relapse compared with intermittent itraconazole.
INTRODUCTION
ONYCHOMYCOSIS is a common disease, and recent population studies have
shown a prevalence of between 2% and 8%.1-3
This disease is more common in older age groups and in selected populations,
such as swimmers and individuals with diabetes mellitus or psoriasis.4-6 Onychomycosis can be
an infection reservoir for dermatomycoses of the adjacent skin, such as interdigital
or plantar ("moccasin type") tinea pedis. Studies have shown that onychomycosis
can have severe impact on quality of life,7
and this disease should not be trivialized.8
For several years treatment of onychomycosis was limited to griseofulvin,
which provided low cure rates and long treatment times. Modern antifungal
agents, such as terbinafine and itraconazole, are significantly more effective
with shorter treatment times. It has previously been demonstrated in a randomized
controlled, multicenter, double-blind, double-dummy study (the Lamisil vs
Itraconazole in Onychomycosis [LION] study) that patients treated with continuous
terbinafine achieved significantly superior mycological and clinical cure
rates compared with patients treated with intermittent itraconazole.9-10
While both itraconazole and terbinafine have proven to be effective
against onychomycosis, very little is known about the long-term maintenance
of cure and relapse rates observed with both drugs.11
The objective of the present study was to examine long-term mycological and
clinical cure rates after treatment with terbinafine and itraconazole for
onychomycosis. Similarly, mycological and clinical relapse rates were examined.
A secondary objective was to evaluate the effect of subsequent treatment with
terbinafine in patients who experienced relapses or failed the original treatment
with terbinafine or itraconazole.
PATIENTS AND METHODS
PROTOCOL
Study Outline
Patients were recruited from a multinational, prospective, randomized,
double-blind, double-dummy study comparing the safety and efficacy of continuous
terbinafine with intermittent itraconazole treatment in onychomycosis. The
clinical courses of 496 patients were followed up to month 18.9-10
Of these 496 patients, 144 from the 3 Icelandic centers were followed up prospectively
(Figure 1). Iceland was the most
suitable country to do this follow-up because there was a large number of
patients enrolled in the trial, and patients were easy to follow-up for long
periods because of the unique geographic location.
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Figure 1. Study flowchart. Of 158 subjects
randomized to treatment, 151 belonged to the intention-to-treat population
and were entered into the study. Of these 151 subjects, 144 could be followed
up for up to 5 years. LION indicates Lamisil vs Itraconazole in Onychomycosis.
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Inclusion and Exclusion Criteria
The study population comprised men and women aged between 18 and 75
years with a clinical diagnosis of onychomycosis of the toenail confirmed
by positive mycological culture and microscopic (potassium hydroxide examination)
findings for a dermatophyte.9-10
All patients belonging to the intention-to-treat population were followed
up prospectively.
Planned Interventions
First Intervention.
Terbinafine was given at a dosage of 250 mg/d for 12 or 16 weeks; itraconazole,
at a dosage of 400 mg/d for 1 week every 4 for 12 (3 cycles) or 16 (4 cycles)
weeks. The 4 treatment groups were compared at baseline, and at weeks 4, 8,
12, 16, 32, 48, and 72 (LION study). The cure rates at month 18 (week 72)
were very similar for both terbinafine groups and both itraconazole groups.
Therefore, in view of the smaller number of patients in the follow-up study,
only 2 treatment groups were considered for prospective analysis, namely,
patients treated with terbinafine (for 12 or 16 weeks) and patients treated
with itraconazole (for 3 or 4 cycles). Patients included in the follow-up
study were checked for clinical and mycological status at approximately 6-month
intervals for up to 5 years (LION Icelandic Extension Study).
Second Intervention.
From month 18 onward, an additional 12-week course of oral terbinafine,
250 mg/d, was offered on clinical signs of reinfection. If necessary, further
additional courses of terbinafine were offered on signs of reinfection or
if previously negative mycological findings became positive with signs of
clinical disease. Patients with positive mycological findings but with normal
nails were not treated.
Mycology and Ethics
All mycological examinations were undertaken at a single laboratory
(Mycology Reference Centre, Leeds, England). The study protocol conformed
to good clinical practice: all patients gave written informed consent to participate,
and the study protocol was subjected to approval by the institutional review
board.
Primary and Secondary Efficacy Criteria
The primary efficacy criterion was the proportion of patients who remained
mycologically cured at the end of follow-up without requiring second intervention
treatment with terbinafine. Mycological cure was defined as negative results
on both microscopy and culture of samples taken from the target toenail. Secondary
efficacy criteria included (1) clinical cure (defined as 100% normal-appearing
nail) at the end of follow-up without the requirement of second intervention
treatment, (2) complete cure defined as mycological plus clinical cure, (3)
clinical and mycological relapse over time, (4) mycological and clinical cure
over time, and (5) the effect of subsequent terbinafine treatment on clinical
and mycological outcome. A mycological relapse was defined as a patient who
achieved mycological cure at month 12 but had mycologically positive test
results at any time thereafter. A clinical relapse was defined as a patient
who achieved clinical cure at month 18 and showed clinical signs of infection
at any time thereafter. The difference in times for the assessment of mycological
and clinical cure can be explained by the slow growth rate of nails. A duration
of 18 months is needed to assess clinical cure, whereas 12 months is adequate
to assess mycological cure.9
Rationale and Methods for Statistical Analysis
All efficacy assessments were based on the intention-to-treat population
defined as all randomized patients who satisfied all inclusion criteria and
had at least 1 primary efficacy measurement at month 6. Treatment comparisons
for mycological cure rate and mycological relapse rate were made by the Fisher
exact test, using the SAS statistical package (SAS Institute Inc, Cary, NC).
The "last observation carried forward" method was used to impute missing observations.12
ASSIGNMENT AND BLINDING
Details on assignment and blinding have been described previously.9 After 18 months the study continued to be blinded
to patients and investigators until an interim analysis was performed in September
1999, after 4 years of follow-up on average.
RESULTS
PARTICIPANT FLOW AND FOLLOW-UP
A total of 268 patients were screened in Iceland (Figure 2), 110 of whom were excluded because of negative results
on mycological examination, withdrawal of consent, protocol violations, or
failure to return to the clinic. The 158 remaining patients were randomized
for treatment, 151 of whom comprised the intention-to-treat population (the
7 patients excluded violated the inclusion or exclusion criteria or did not
have sufficient follow-up). Of these 151 patients, 143 completed the first
18 months of the study, and the clinical courses of 144 were followed up to
58 months. The median duration of follow-up was 54 months (range, 8-58 months),
with 142 (94%) of the 151 patients followed up for more than 43 months. The
treatment groups were comparable with regard to demographics and the extent
and duration of nail disease at baseline (Table 1).
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Figure 2. Distribution of participants in
the Lamisil vs Itraconazole in Onychomycosis Icelandic Extension Study.
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Table 1. Baseline Characteristics
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CAUSAL AGENTS
The dermatophyte species isolated at screening were Trichophyton rubrum alone (146 patients [97%]), T rubrum plus a nondermatophyte mold (4 patients [3%]), and Trichophyton mentagrophytes alone (1 patient [1%]).
LONG-TERM CURE RATES AFTER FIRST INTERVENTION
At the end of follow-up, 34 (46%) of the 74 patients originally treated
with terbinafine had negative mycological examination results without the
need for a second intervention (Table 2). Significantly fewer patients treated with itraconazole maintained
mycological cure (10 [13%] of 77; P<.001). When
clinical cure rates were considered, 31 (42%) of the 74 terbinafine-treated
patients remained clinically cured at the end of follow-up compared with 14
(18%) of the 77 itraconazole-treated patients (P<.002; Table 2). Regarding complete cure, significantly
more patients treated with terbinafine maintained complete cure at the end
of follow-up without the need for a second intervention (P<.005; Table 2).
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Table 2. Mycological and Clinical Cure Rates*
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RELAPSE RATES
After 12 months, 57 (77%) of the 74 patients taking terbinafine had
achieved mycological cure, and the corresponding rate for itraconazole was
32 (42%) of 77 patients. Six months later (at 18 months), 5 (9%) of 57 terbinafine-treated
patients and 7 (22%) of 32 itraconazole-treated patients had relapsed mycologically.
The relapses in the itraconazole-treated patients continued to increase between
months 18 and 36 (Figure 3), while
relapses in terbinafine-treated patients increased only slightly. After 31
to 36 months, very few mycological relapses were seen in both groups. At the
end of the study, significantly fewer terbinafine-treated patients had experienced
a mycological relapse compared with itraconazole-treated patients (13 [23%]
of 57 vs 17 [53%] of 32; P<.01) Clinical relapse
showed a similar pattern. At the end of the study, 8 (21%) of the 39 terbinafine-treated
patients had a clinical relapse, while the corresponding relapse rate for
the itraconazole-treated patients was 48% (14 of 29 patients) (P<.05; Figure 3).
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Figure 3. Mycological (A) and clinical (B)
relapse rates.
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RESPONSE TO SECOND INTERVENTION WITH TERBINAFINE
Patients with clinical signs of onychomycosis after 18 months were offered
treatment with terbinafine in an open manner. Details about the 72 patients
receiving second intervention treatment are given in Table 3. At the end of follow-up, 23 (92%) of 25 patients who originally
received terbinafine as first intervention and 40 (85%) of 47 patients who
originally received itraconazole achieved mycological cure. Regarding clinical
cure, 19 (76%) of 25 patients who originally received terbinafine and 36 (77%)
of 47 patients who received itraconazole were clinically cured at the end
of follow-up. All 6 patients originally treated with terbinafine who did not
achieve clinical cure had 10% or less dystrophy at the end of follow-up. Among
the patients originally treated with itraconazole, 5 of 11 patients who did
not achieve clinical cure had 10% or less dystrophy at the end of follow-up.
Complete cure was achieved in 52 (72%) of 72 patients overall.
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Table 3. Subjects Receiving Second Intervention With Terbinafine at
Month 18
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COMMENT
Many studies have addressed the efficacy of modern antifungal drugs
on onychomycosis.13-19
Most studies have concentrated on 9 to 12 months' outcome. Few studies have
addressed the long-term efficacy or relapse rates after antifungal treatment.
Considering that toenails can take 12 to 18 months to grow out, many clinicians
consider that 1 year is too short to assess clinical effectiveness.11 Most of the studies that have followed the clinical
courses of patients beyond 12 months have been small with no possibility for
meaningful comparisons between treatment groups, have not followed the clinical
courses of patients beyond 3 years, or have used different end points for
cure. Few studies have addressed relapse rates.20-23
In the present study, we have shown that terbinafine achieves significantly
higher long-term mycological and clinical cure rates than itraconazole in
onychomycosis. To our knowledge, this study represents the longest prospective
follow-up of patients treated for toenail onychomycosis. The study was done
in Iceland, and it is possible that the results would differ with a more heterogeneous
study population. We do not find this likely. The patients were recruited
from the multinational LION study, and in this study no difference in cure
rates was found between individual countries.9-10
It can be argued that the cure rates observed at 54 months are suboptimal,
with 34 (46%) of the 74 terbinafine-treated and 10 (13%) of the 77 itraconazole-treated
patients achieving mycological cure. However, toenail onychomycosis is recognized
to be a difficult condition to treat, and most of the patients studied had
long-standing and widespread disease as shown by the duration of disease and
number of nails involved. Moreover, we used very stringent criteria for analysis,
taking the intention-to-treat population as the denominator for assessment
of long-term effectiveness. The differences between itraconazole- and terbinafine-treated
patients, however, are marked and of clinical importance regarding treatment
decisions.
Interestingly, we have demonstrated that the relapse rate is significantly
higher among patients treated with itraconazole (Figure 3). It is striking to see that itraconazole-treated patients
experience a rapid increase in mycological relapses up to months 31 to 36,
with a stable condition thereafter. In the terbinafine-treated patients the
situation is more stable with constant and low relapse rates during the entire
follow-up period. It is well recognized that both itraconazole and terbinafine
can persist for months after treatment at clinically relevant concentrations
in treated nails.24 Terbinafine is primarily
fungicidal in its mode of action as opposed to itraconazole, which is primarily
fungistatic. It is tempting to speculate that the fungicidal activity of terbinafine
enables it to kill the fungus more rapidly at low concentrations and that
this may account for the lower relapse rate observed in this study. Also,
the concentration of terbinafine achieved in the nails is much higher relative
to the concentration required to kill the fungus than it is for itraconazole.24 With current techniques, it is impossible to distinguish
between a reinfection and a recurrence of a previous infection. Because the
drugs have disappeared from the nails at this time, it is very unlikely that
the reinfection rate is different between the 2 patient groups. The only logical
explanation for the differences between the 2 groups is that the itraconazole-treated
patients experience more recurrences (not reinfections) than the terbinafine-treated
patients.
The results of the second intervention with terbinafine show that many
patients who fail to respond to conventional 3- to 4-month treatment with
terbinafine or 3- to 4-cycle treatment with itraconazole can be treated successfully
with prolonged treatment or additional courses of terbinafine. This is valid
for patients failing the initial treatment with terbinafine or itraconazole.
It is likely that a subgroup of patients who fails to respond adequately to
conventional treatment needs a more individualized treatment approach. In
this study an individualized approach was used in a difficult-to-treat subgroup
of patients who failed to respond to conventional treatment, and good cure
rates were achieved. Further research is needed to optimize cure rates in
onychomycosis. Patients likely to respond poorly to conventional treatment
could benefit from a more individualized approach. Considering the cost of
treatment with antifungal agents today, more research is needed to identify
such patients with refractory disease.
AUTHOR INFORMATION
Accepted for publication May 16, 2001.
This research project was funded in part by an unconditional research
grant from Novartis Pharmaceuticals Corporation, East Hanover, NJ (Novartis
manufactures terbinafine).
We express our sincere appreciation to Des Curran, PhD, at ICON Clinical
Research, Dublin, Ireland, who did the statistical analysis, to Farid Kianifard,
PhD, to Ercem Atillasoy, MD, at Novartis Pharmaceuticals Corporation, for
clinical and statistical advice, and to the staff of the Mycology Reference
Centre, Leeds, England, who undertook the mycological investigations.
Corresponding author and reprints: Bárður Sigurgeirsson,
MD, PhD, Húðlæknastöðin, Smáratorg 1, 200 Kópavogur, Iceland
(e-mail: bsig{at}isholf.is).
From the Department of Dermatology, University of Iceland and Landspitali
University Hospital, Reykjavik, Iceland (Drs Sigurgeirsson and Ólafsson);
Húðlæknastöðin, Dermatology Center (Dr Steinsson); the
Department of Dermatology, Mulhouse Hospital, Mulhouse, France; Clinical Research,
Novartis Pharma AG, Basel, Switzerland (Dr Paul); Clinical Research, Novartis
Pharmaceutical Corporation, East Hanover, NJ (Dr Billstein); and Mycology
Reference Centre, University of Leeds and General Infirmary, Leeds, England
(Dr Evans).
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