aBoni E Elewski, MD; bTracey C. Vlahovic, DPM; cAndrew Korotzer, PhD
aDepartment of Dermatology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama
bTemple University School of Podiatric Medicine, Philadelphia, Pennsylvania
cValeant Pharmaceuticals North America LLC, Bridgewater, New Jersey
Disclosure: Dr Elewski is an advisor for Valeant Pharmaceuticals and investigator for Valeant Pharmaceuticals and Anacor. Dr Vlahovic was a principle investigator in the pivotal trials with efinaconazole topical solution, 10%. Dr Korotzer is an employee of Valeant Pharmaceuticals.
Abstract
Background: The current definition of complete cure is considered too stringent to reflect the true benefit of onychomycosis treatment seen in general practice and may limit the use of newer topical agents in mild-to-moderate disease. In addition, outcomes reported in clinical trials do not consistently report secondary endpoints, making data comparison difficult. Methods: The authors review the clinical data reported on two new topical antifungals, efinaconazole and tavaborole, in light of the latest thinking of more practical approaches to assess improvement and treatment success. Results: Almost 20 percent (19.7%) of patients treated with efinaconazole had absence of clinical signs, and almost a third (31.6%) had ?10 percent affected toenail and mycologic cure at Week 52. Cure rates for tavaborole (<10% affected toenail and mycologic cure) were 15.3 percent and 17.9 percent at Week 52. With both topical treatments, cure rates were higher when only negative culture was considered. Conclusion: These clinical cure rates likely better reflect the efficacy we see in practice. It is probable that efficacy would be further improved with longer treatment courses and/or longer follow-up periods and appropriate prophylactic strategies. This clinical judgment is predicated by any risk of nonadherence or disease recurrence. J Clin Aesthet Dermatol. 2016;9(11):34–39
It is well-recognized that while complete cure (0% clinical involvement of target toenail and both negative potassium hydroxide [KOH] examination and fungal culture) may be important from a regulatory perspective, it is likely too stringent from a practical perspective and may limit the use of new onychomycosis treatments due to misconceptions over likely efficacy. Despite much discussion on the topic, there remains no agreement on clinical criteria defining resolution of onychomycosis.[1],[2]
The clinical data we have on the treatment of onychomycosis with topical antifungals is problematic for two main reasons—different definitions of treatment success have been used as secondary endpoints, and studies may have been too short either in terms of treatment duration or follow-up to reflect true nail pathology.[2] As a result, the true clinical benefit of the newer topical agents is unclear. In addition, studies focus on efficacy at the great toenail, whereas in practice, a number of toenails are usually affected, suggesting efficacy should be based on all involved onychomycotic toenails.[3]
In the authors’ study, they review the clinical data reported on efinaconazole and tavaborole in light of criteria previously proposed for onychomycosis clinical cure. In addition, they review published data on long-term treatment and follow-up with other antifungals that may provide additional insights into expected clinical outcomes with these newer agents.
METHODS
A number of definitions of treatment success in onychomycosis exist (Table 1 ). Data reported from the pivotal Phase 3 studies on efinaconazole and tavaborole were reviewed in conjunction with two alternative criteria proposed for clinical cure:1
• 100 percent absence of clinical signs of onychomycosis (mycology not required); or
• negative mycological laboratory results with one or more of the following clinical signs—distal subungual hyperkeratosis or onycholysis leaving less than 10% of nail plate affected or nail-plate thickening that does not improve with treatment because of comorbid condition.
In addition, the authors included more recent recommendations suggesting that the absence of clinical signs following an adequate washout period, coupled with negative culture, with or without negative microscopy, should be considered as onychomycosis cure.[2] Data on longer term treatment of onychomycosis with other antifungals was also reviewed to determine whether better clinical outcomes might be achieved.
RESULTS
Clinical cure. Reported complete cure rates (0% clinical involvement of the target toenail and mycologic cure [negative KOH examination, and negative fungal culture of the target toenail sample]) in the pivotal clinical studies were 6.5 and 9.1 percent (tavaborole),4 and 15.2 and 17.8 percent (efinaconazole)5 at Week 52 (intent-to-treat populations, last observation carried forward [LOCF]). With efinaconazole, complete cure rates increased by 16 percent over the four-week follow-up period.
At Week 52, 19.7 percent of patients treated with efinaconazole had a clear nail (0% affected target toenail area unrelated to mycologic cure); whereas 31.8 percent of patients had ?[5] percent affected toenail and negative culture, and almost a third of patients (31.6%) had ?10 percent affected toenail and mycologic cure (all data is pooled, intent-to-treat population, LOCF) (Table 2).
A completely or almost clear nail (in this case defined as <10% affected toenail) and mycologic cure was reported in 15.3 and 17.9 percent of patients treated with tavaborole and in 24.6 and 25.3 percent of patients with negative culture at Week 52 (individual study data, intent-to-treat population, LOCF) (Table 2).[4]
Longer treatment duration. We are not aware of any well-designed clinical studies with oral or topical treatment durations of longer than 12 months.
An open, randomized study in patients with severe dermatophyte toenail onychomycosis with matrix involvement compared 15 months of once-weekly amorolfine lacquer in combination with either 6 or 12 weeks daily terbinafine with terbinafine monotherapy for 12 weeks.[6] Patients were followed up for a total of 18 months. A retrospective analysis of cure rates with oral antifungals conducted in Japan, where low-dose continuous treatment with itraconazole was standard practice, estimated through multiple regression analysis that the treatment duration (in months) to cure onychomycosis was 3.92+0.161 [age (years)] + 0.635 [number of infected toenails]. Applying this model to the studies on efinaconazole and tavaborole, where the average age was 50 and number of infected toenails 3, would predict a treatment duration of about 60 weeks. However, dropout rates in the Japanese study were high (38.1%), highlighting the problems of patient adherence with long-term treatment.[7]
Longer follow-up periods. Higher cure levels following longer follow-up periods have been reported.[8–10] The LION (Lamisil vs. Itraconazole in Onychomycosis) study included four treatment arms (terbinafine continuous for 12 or 16 weeks, and itraconazole 3 or 4 months intermittent). Patient follow-up extended to Week 72 with continued increases in mycologic cure rates, the primary efficacy endpoint, from Week 48 to Week 72.8 A multicenter comparative study of two formulations of ciclopirox nail lacquer in mild-to-moderate onychomycosis included daily treatment for 48 weeks and a 12-week follow-up period.[9] Complete cure rates for the marketed formulation and a new hydro lacquer based on hydroxypropyl chitosan technology were 3.2 and 5.7 percent at Week 48, respectively (intent-to-treat population). In both groups, complete cure rates continued to increase through the follow-up period to 5.8 and 12.7 percent, respectively, by Week 60 (an 81% and 123% increase).[9] A multicenter, open-label comparative, study of amorolfine nail lacquer once weekly for 12 months plus terbinafine once daily for three months, or terbinafine alone once daily for three months incorporated a six-month and 15-month treatment-free follow-up, respectively.[10] Treatment success was defined as the combination of clinical cure (i.e., disappearance of all lesions on each nail or residual disease of no more than 10% of the original total diseased surface) and negative mycology comprising both negative direct microscopy and negative culture. Efficacy in the combination treatment group continued to increase throughout the follow-up with a 20-percent increase in treatment success over the six-month period. Efficacy in the terbinafine-only group also continued to increase post-treatment, peaking at 12 months. There was no further increase in the following six-month period.[10]
Longer follow-up periods may be complicated with the potential for relapse or recurrence, although long-term follow-up studies tend not to report data on shorter-term (3–6 month) washout periods. One study reported an 8.3-percent relapse rate within the first year following successful treatment with terbinafine or itraconazole.[11] The LION study reported a mycological relapse of 22 percent (itraconazole) and nine percent (terbinafine) at Month 18 following a 3- to 4-month continuous (terbinafine) or intermittent (itraconazole) treatment.[12]
DISCUSSION
Clinical cure rates for efinaconazole and tavaborole using the proposed definitions are much higher than the complete cure rates reported in the literature and may better reflect the efficacy we see in clinical practice. Almost 20 percent (19.7%) of patients treated with efinaconazole had absence of clinical signs at Week 52, and almost a third (31.6%) had ?10 percent affected toenail and mycologic cure. Clinical cure (<10% affected toenail and mycologic cure) was reported in 15.3 and 17.9 percent of patients treated with tavaborole at Week 52.[4]
Recently it has been suggested that the absence of clinical signs following an adequate washout period, coupled with negative culture, with or without negative microscopy, should be considered as onychomycosis cure.[2] A completely or almost clear nail with negative culture was reported in 24.6 and 25.3 percent of patients treated with tavaborole and in 31.8 percent of patients treated with efinaconazole, although the definition of completely or almost clear nail (<10% affected toenail versus ?5% affected toenail, respectively) differed.
The impact of an adequate washout period on the efficacy of efinaconazole or tavaborole is unknown. It has been suggested that extending the length of treatment beyond 48 weeks and increasing the washout period to at least 3 to 6 months would allow a more accurate interpretation of mycological outcome, afford more time for nails to grow out, eliminate nonviable fungal elements, and provide more time for the nail’s appearance to improve.[2] In the pivotal studies, treatment duration was only 48 weeks, with a four-week follow-up. During this washout period a 16-percent increase in complete cure rates were seen with efinaconazole. Data from other studies suggest that extending the follow-up period to 3 to 6 months should afford even better results; however, the risk of relapse or recurrence would be greater without empirical prophylaxis with topical antifungals.
A stimulation analysis suggested that a treatment duration of 18 months is required to achieve a meaningful and demonstrable clinical benefit.13 It is unknown whether clinical cure rates would be greater with an extended follow-up or longer treatment course. There is a marked difference in the 36- to 48-week trajectories and 48- to 52-week trajectories depending on whether mycologic cure is required, suggesting that a longer treatment course would provide better clinical outcomes than a longer follow-up period. However, a longer treatment course is likely to increase the adherence challenges of chronic treatment.
Adherence data in onychomycosis are limited, but well-documented with other chronic therapies. Two studies suggest one in four patients may not complete a course of therapy. A Chinese study reported an overall adherence rate of topical antifungals treatment of 23.9 percent (92/385). Age, gender, and other factors (level of disease awareness, occupation, course of disease, personal income, inconvenience in accessing treatment, forgetfulness, impatience in seeing results, application process, and quality of life) were significant influencing factors.[14] In a prospective study by German investigators of onychomycosis patients who underwent combined treatment of nail abrasion and application of topical antifungal also reported a nonadherence rate of 24 percent, with a greater frequency in men (31.6%) and pensioners (42.0%).[15]
Longer-term follow-up increases the risk of disease recurrence or relapse being noted, but this finding is likely to be of positive benefit as additional treatment strategies could be instigated should onychomycosis recur. Data on recurrence rates with topical therapy are also extremely limited. One study retrospectively studied six patients cured following amorolfine treatment and reported a recurrence rate of 33.3 percent after one year (similar to that observed with itraconazole and terbinafine in the same study), although no distinction was made as to whether this was the re-emergence of existing disease or a new infection.[16]
Several factors have been suggested to play a role in the high incidence of recurrence, including genetic predisposition, athletic activity, and use of health clubs and spas. In the elderly, physical trauma may play a role. Patients with concomitant disease (e.g., peripheral arterial disease, diabetes mellitus) or those who are immunocompromised or immunosuppressed (e.g., those with human immunodeficiency virus/acquired immunodeficiency syndrome) may be more susceptible to disease recurrence.[17] Only the co-existence of diabetes has been shown to have a significant impact.[17] These data suggest that if longer treatment courses or follow-up are thought to be important, caution would be advised in elderly male patients and those with co-existing diabetes.
CONCLUSION
Clinical cure rates with efinaconazole are two- to threefold greater than the more stringent complete cure rates reported in the literature and better reflect the efficacy we see in general practice. It is likely that efficacy would be further improved following a longer course of therapy (up to 18 months); however, the likelihood of poor adherence, especially in males and elderly patients would need to be evaluated. Alternatively, a longer follow-up period with appropriate prophylaxis to minimize recurrence may suffice. Acknowledgments The authors acknowledge Brian Bulley, MSc, of Konic Limited for medical writing support. Valeant Pharmaceuticals North America LLC funded Konic’s activities pertaining to this manuscript. Andrew Korotzer provided additional unpublished data on efinaconazole.
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