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Recurrences of Dermatophyte Toenail Onychomycosis during Long-Term Follow-up after Successful Treatments with Mono- and Combined Therapy of Terbinafine and Itraconazole Aditya K. Gupta, Elizabeth A. Cooper, and Maryse Paquet Background: The influence of dosing regimens on the recurrence rates of onychomycosis has not been investigated. Objective: To compare recurrence rates for toenail dermatophyte onychomycosis between four dosing regimens. Methods: A prospective, investigator-blinded, long-term follow-up (1.25 to 7 years postenrolment) study of the following regimens was undertaken with or without booster therapy at week 36: overlapping continuous itraconazole and terbinafine (COMBO), continuous terbinafine (CTERB), intermittent terbinafine (TOT), and pulsed itraconazole (III). Results: One hundred six mycologically and 43 completely cured participants at week 48 were included. Recurrence rates (RR) for mycologically and completely cured participants were respectively termed mycologic recurrence (MRR) and complete cure recurrence (CRR) rates. No statistically significant difference was detected between the four regimens for the two rates. However, lower MRRs were obtained for CTERB (32%) and TOT (36%) compared to III (59%) and COMBO (57%). When participants who received booster therapy were excluded from the analysis, the MRR was lower for CTERB (21%) compared to TOT (39%). Conclusions: Itraconazole therapy was associated with higher RRs than terbinafine therapy. Combined therapy did not reduce the RRs compared to monotherapies. A difference might exist between continuous and intermittent antifungal regimens, but additional randomized clinical trials are needed for confirmation. Contexte: L’incidence de la posologie sur le taux de reápparition de l’onychomycose n’a jamais e´te´ e´tudieé. Objectif: L’e´tude visait a` comparer le taux de reápparition de l’onychomycose a` dermatophytes sur ongle d’orteil entre quatre sche´mas posologiques. Me´thode: Une e´tude prospective, meneé a` l’insu des chercheurs et comportant un suivi prolonge´ (1.25 a` 7 ans apre`s l’inscription) a porte´ sur les sche´mas posologiques suivants, avec ou sans traitement de rappel a` la 36e semaine: administration continue d’itraconazole et de terbinafine avec pe´riode de chevauchement (COMBO); administration continue de terbinafine (CTERB); administration intermittente de terbinafine (TOT); et administration pulseé d’itraconazole (III). Re´sultats: Cent six participants conside´re´s comme mycologiquement gue´ris, dont 43 conside´re´s comme comple`tement gue´ris, a` la 48e semaine ont e´te´ retenus pour l’e´tude. Les taux de reápparition chez les sujets mycologiquement gue´ris (mg) et chez les sujets comple`tement gue´ris (cg) ont e´te´ respectivement de´signe´s taux de reápparition mycologique (TRmg) et taux de reápparition (TRcg). Aucun ećart statistiquement significatif n’a e´te´ releve´ entre les quatre sche´mas posologiques au regard de ces deux taux; cependant, les TRmg les plus faibles ont e´te´ enregistre´s dans les groupes de traitement CTERB (32%) et TOT (36%) comparativement aux groupes de traitement III (59%) et COMBO (57%). Lorsque les participants qui avaient reçu un traitement de rappel ont e´te´ ećarte´s de l’analyse, le TRmg e´tait plus faible dans le groupe CTERB (21%) que dans le groupe TOT (39%). Conclusions: Le traitement par l’itraconazole a e´te´ associe´ a` un TRcg plus e´leve´ que le traitement par la terbinafine. La bithe´rapie n’a pas permis de diminuer le taux global de reápparition comparativement a` la monothe´rapie. Il pourrait exister une diffe´rence entre

From the Division of Dermatology, Department of Medicine, University of Toronto, Toronto, ON, and Mediprobe Research Inc., London, ON. Presented at the American Academy of Dermatology 70th Annual Meeting, March 2012, San Diego, CA.

Address reprint requests to: Aditya K. Gupta, MD, PhD, FRCPC, 645 Windermere Road, London, ON N5X 2P1; e-mail: agupta@execulink. com.

DOI 10.2310/7750.2013.12088 # 2013 Canadian Dermatology Association

Canadian Dermatology Association | Journal of Cutaneous Medicine and Surgery, Vol 17, No 3 (May/June), 2013: pp 201–206

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les sche´mas d’administration continue et intermittente d’antifongiques, mais, pour en eˆtre suˆr, il faudrait mener d’autres essais cliniques a` re´partition aleátoire.

NYCHOMYCOSIS is a fungal infection of the nail unit. The most commonly isolated microorganism is the dermatophyte fungus Trichophyton rubrum. In combination with other dermatophytes, T. rubrum accounts for approximately 90% of all fungal nail infections.1 Estimates of the prevalence of onychomycosis in North America vary from 6.5 to 13.8%.2–4 The systemic antifungal therapies most frequently used to treat onychomycosis are terbinafine and itraconazole. Although monotherapy with terbinafine or itraconazole has proven effective, a substantial proportion of patients do not experience a complete and lasting cure. As many as 25 to 50% of patients encountered in clinical practice are classified as treatment failures.5,6 Furthermore, a substantial number of cured patients experience a recurrence of the infection.7 Recurrences might be due to the presence of resistant conidia in the nail.8 Indeed, conidia have been shown to be less susceptible to the antifungal action of itraconazole and terbinafine than hyphae for dermatophytes9,10 and nondermatophyte molds.11 The development of new therapies is infrequent, so different regimens of currently available treatments should be investigated to reduce recurrence rates (RRs). We hypothesize that pulse therapy may allow the antifungal concentration to rise and fall in a controlled pattern to allow protected structures (conidia) to germinate and become susceptible to treatment to prevent recurrence. Moreover, Biancalana and colleagues also reported a synergic action between itraconazole and terbinafine on both conidia and hyphae.11 Thus, a combined therapy might result in better eradication of conidia and prevent recurrence of infection. To compare RRs with continuous and intermittent monotherapies and combined therapy of terbinafine and itraconazole, participants successfully cured in previously published clinical trials of dermatophyte toenail onychomycosis12 were followed up.

O

Methods Study Design

N N N N

Itraconazole 200 mg/day for weeks 1 to 4 and terbinafine 250 mg/day for weeks 3 to 6 (2-week overlap of itraconazole and terbinafine) (COMBO) Continuous terbinafine 250 mg/day for 12 weeks (CTERB) Intermittent terbinafine (250 mg/day for 4 weeks on, 4 weeks off, 4 weeks on) (TOT) Pulsed itraconazole (one pulse 5 200 mg twice daily for 7 days on, 21 days off) for three pulses (III)

At week 36, patients meeting one or more of the following criteria were eligible for booster therapy: , 50% improvement of the affected target toenail area since baseline or , 3 mm outgrowth of normal-appearing toenail compared to baseline; positive potassium hydroxide (KOH) findings and/or dermatophyte grown in culture at the week 24 evaluation; or nail plate thickness $ 3 mm at week 36. Patients eligible for booster therapy in the CTERB, COMBO, and TOT groups received terbinafine 250 mg/day for 4 weeks. The eligible patients in the III group received itraconazole 200 mg twice daily for 1 week. Patients To be included in this analysis, the participants had to be (1) mycologically cured at 48 weeks after the beginning of therapy based on a last observation carry forward (LOCF) analysis and (2) both clinically and mycologically assessed after week 48. Participants were excluded if they had any protocol violations (for details on protocol, see Gupta and colleagues12). Efficacy Variables

Participants from a previously published clinical trial of toenail onychomycosis caused by dermatophytes12 were followed up for as long as possible, regardless of clinical or mycologic outcomes. Visual and mycologic assessments of 202

infection of target toenails were blinded and conducted approximately every 12 to 24 weeks and continuing from week 48 onward to a final observation point between 1.25 and 7 years postenrolment. This prospective study started in April 1996 and ended in December 2004. The participants were treated with the following regimens (Figure 1):

The end points of the follow-up phase were the proportions of participants with mycologic recurrence and recurrence (clinical and/or mycologic) at a post–week 48 visit. Mycologic recurrence was defined to occur only


Onychomycosis Recurrences in Long-Term Follow-up

Figure 1. Dosing regimens for the four treatment groups. The four treatment regimens used in the study, overlapping continuous combined regimen of itraconazole and terbinafine (COMBO), continuous terbinafine (CTERB), intermittent terbinafine (TOT), and pulsed itraconazole (III), are illustrated. A booster therapy was administered to participants meeting clinical and/or mycologic criteria at week 36.

after a subject had achieved mycologic cure (KOH and dermatophyte culture negative) at week 48 (LOCF), and KOH and/or culture for dermatophytes were positive at a post–week 48 visit. Recurrence was defined to occur only after a subject had achieved complete cure (negative KOH and dermatophyte culture, with 0% affected area in the target toenail) at week 48 (LOCF), and the following conditions were observed at a post–week 48 visit: KOH and/or culture for dermatophytes were positive and/or the affected area of nail was . 0%.

one-way analysis of variance, followed by Bonferroni post hoc analysis. Chi-square testing was used to compare the sex of participants, the proportions of participants who received booster therapy, the organisms at baseline, and the RRs to the null hypothesis that there was no difference between treatment groups. In the event that the chi-square test showed significance, a z-test for two proportions (two-tailed) was used to investigate differences in cure rates between groups. A significance level of .05 was used for all statistical tests.

Results Statistical Analysis Data analysis was conducted with SPSS (SPSS Inc, Chicago, IL) and GraphPad (GraphPad Software, La Jolla, CA). Comparisons for mean age and mean percentage of toenail involvement at baseline, as well as the mean times of followup in the different treatment groups, were performed using

A total of 106 participants mycologically cured at week 48 and followed up (23 COMBO, 25 CTERB, 36 TOT, and 22 III) were included in our analyses. The baseline characteristics of these participants and the mean follow-up time for the four regimens were similar with the exception of the mean percentage of infected area at baseline, which was


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Table 1. Characteristics of the Participants Mycologically Cured at Week 48 and Followed Up Characteristic

COMBO

CTERB

TOT

III

Total

Number of participants Number of participants who received booster therapy at week 36, n (%) Mean age 6 SD (yr) Gender (% male) Mean percentage of infected nail area at baseline 6 SD (%) Organisms at baseline, n (%) T. rubrum T. mentagrophytes Mean follow-up time 6 SD (wk) Range of follow-up time (wk)

23 11 (48)

25 11 (44)

36 8 (22)

22 9 (41)

106 39 (37)

55 6 12 74 48 6 25*

57 6 11 52 65 6 27

50 6 17 61 68 6 23

61 6 15 77 62 6 30

55 6 15 65 61 6 26

18 (72) 7 (28) 123 6 48 60–216

33 (92) 3 (8) 123 6 88 60–356

19 (86) 3 (14) 127 6 45 72–224

88 (83) 18 (17) 121 6 62 60–356

18 (78) 5 (22) 109 6 36 60–180

COMBO 5 overlapping continuous combined regimen of itraconazole and terbinafine; CTERB 5 continuous terbinafine; III 5 pulsed itraconazole; TOT 5 intermittent terbinafine. *Significantly different than TOT; post hoc analysis p 5 .028.

significantly lower in the participants with the COMBO regimen compared to the TOT regimen (Table 1). The percentage of participants who qualified for and received booster therapy was lower for the TOT regimen (see Table 1). Of the 106 participants, 43 were completely cured at week 48 (9 COMBO, 10 CTERB, 18 TOT, and 6 III). Mycologic recurrence was found to occur in 43% (46 of 106) of all subjects. Mycologic recurrence rates (MRRs) were similar for the CTERB (32%) and TOT (36%) regimens, as well as for the III (59%) and the COMBO (57%) regimens (Table 2). About half (22 of 43; 51%) of the participants completely cured had recurrence post–week 48. The recurrence rates for complete cure (CRRs) by regimen were similar and ranged from 40 (CTERB) to 67% (COMBO) (see Table 2). Similar RRs were generally obtained when participants who received booster therapy were excluded from the analyses. However, the MRRs for CTERB (21%) and III (46%) were lower when the participants requiring booster were excluded. No statistically

significant difference was detected between the four treatment groups (see Table 2).

Discussion An overall RR of 40 to 53% of previously ‘‘cured’’ subjects presenting with renewed evidence of onychomycosis was obtained. This high RR may be due to specific treatment regimens used in our study. Indeed, higher MRRs were obtained for two of the four regimens (ie, COMBO, 57%, and III, 59%) compared to the continuous and pulsed terbinafine regimens (CTERB, 32%, and TOT, 36%). No statistically significant difference was found between the four groups, probably due to their small sample sizes. A recent meta-analysis of studies investigating RRs following successful treatment of toenail onychomycosis with continuous (two studies) or pulsed (three studies) itraconazole and continuous terbinafine showed that itraconazole therapy resulted in significantly higher RRs

Table 2. Recurrence Rates Rate

COMBO

All participants, n (%) Mycologic recurrence 13/23 (57) Recurrence 6/9 (67) Participants who did not receive booster therapy, Mycologic recurrence 7/12 (58) Recurrence 4/6 (67)

CTERB

TOT

III

Chi-square (p Value)

Total

8/25 (32) 4/10 (40) n (%) 3/14 (21) 4/9 (44)

13/36 (36) 9/18 (50)

13/22 (59) 3/6 (50)

.085 .711

46/106 (43) 22/43 (51)

11/28 (39) 9/17 (53)

6/13 (46) 3/6 (50)

.273 .865

27/67 (40) 20/38 (53)

COMBO 5 overlapping continuous combined regimen of itraconazole and terbinafine; CTERB 5 continuous terbinafine; III 5 pulsed itraconazole; TOT 5 intermittent terbinafine.

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than terbinafine.13 Our RRs for continuous terbinafine and intermittent itraconazole are consistent with this analysis. This difference in RRs between the two antifungal agents might be partially explained by the fact that terbinafine is better than itraconazole at suppressing arthospore (conidia) production in T. rubrum14 and/or the difference in their mechanisms of action (ie, fungicidal vs fungistatic).13 The combined regimen in this study used shorter (4 weeks instead of 12 weeks) but overlapping continuous regimens for both itraconazole and terbinafine for 6 weeks of therapy. This regimen had the highest percentage of participants who received booster therapy at week 36 (48%) and the highest RRs overall (57–67%). A different combined regimen using sequential intermittent regimens (ie, two pulses of itraconazole [1 week on/3 weeks off] followed by one pulse of terbinafine [1 week on/3 weeks off] for 12 weeks of therapy) was previously investigated and compared to three pulses of terbinafine (1 week on/3 weeks off).15 This study also gave booster therapy (1 week terbinafine) if needed between weeks 24 and 48. This sequential intermittent combined regimen had a similar percentage of participants who received booster therapy (54.7% vs 51.1%) and RRs at week 72 (13.3% vs 12.2%) similar to those of the TOT regimen. Together, these observations suggest that combined therapy of itraconazole and terbinafine may not result in lower RRs compared to monotherapies. We hypothesized that lower RRs might be obtained with intermittent regimens compared to continuous regimens. In our study, no difference was observed between continuous and intermittent terbinafine when participants who received booster therapy were included in the analysis. The addition of the booster therapy, which acts as a pulse, to the continuous terbinafine regimen makes it difficult to conclude on the effect of intermittent versus continuous regimen. Exclusion of the participants who received the booster therapy suggests that, contrary to our hypothesis, continuous terbinafine (21%) was associated with a lower MRR than intermittent terbinafine (39%). RRs ranging from 6 to 30% and 12.2 to 15% have been published for the continuous terbinafine5,7,16–21 and intermittent terbinafine regimens.15,19 In the only study directly comparing continuous and intermittent terbinafine, similar RRs were observed for the two regimens.19 To our knowledge, differences in RRs between continuous and intermittent itraconazole therapy have not been investigated. Published RRs for continuous and intermittent itraconazole range from 27 to 100%18,20,22 and 0 to 53%,5,7,19,23–25 respectively. Thus, it is possible for itraconazole therapy that a pulse regimen could result in fewer recurrences of onychomycosis than a continuous regimen. For both terbinafine and

itraconazole, no conclusion could be reached on the differences between intermittent and continuous regimens, and this issue still needs further investigation. In light of the evidence presented here and by other authors, clinicians and patients need to be aware of the high risk of recurrence when considering any systemic antifungal treatment for onychomycosis. Although we did not detect any statistically significant differences in RRs with regard to different treatments, these differences may be detectable in larger studies with greater statistical power. Relative rates of recurrence from different treatment regimens will be of great value in determining if an optimal drug and dosing regimen exists as RRs significantly impact long-term cure in onychomycosis. For convenience, this study referred to any detection of infection following a cure as a ‘‘recurrence.’’ Recurrence of onychomycosis includes both relapse and reinfection. Typically, relapse refers to a recurrence of the previous infection, which has remained clinically and mycologically undetected in the nail, as opposed to a reinfection, where the nail is recolonized by either the previous strain or species of fungus or a new strain or species of fungus. At the time this study was performed, genetic identification of dermatophyte species and strains was not available, and this study was not able to distinguish between relapse and reinfection. Future investigations using genetic strain typing methods may be able to provide a clearer picture of recurrence: the distinction may be significant to establish as relapse indicates that insufficient therapy is being given and a false ‘‘cure’’ is being declared, whereas reinfection may indicate that other nontreatment methods may need to be instituted to protect a truly cured nail.

Conclusion Long-term follow-up studies of toenail onychomycosis have statistical limitations due to their final small sample sizes. Despite these limitations, we can conclude that combined itraconazole and terbinafine therapy does not decrease the RR for toenail onychomycosis caused by dermatophytes. In our study, continuous terbinafine was associated with a lower relapse rate than intermittent terbinafine; however, further investigations on RRs for intermittent and continuous regimens are required before we can reach definitive conclusions.

Acknowledgment Financial disclosure of authors and reviewers: None reported.


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