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The Impact Of New Topical Antifungals On Onychomycosis Management
These authors share their experience with the efficacy of new topical agents for onychomycosis, when to combine topical and oral therapy, and what the future may bring.
Onychomycosis is a superficial fungal infection of the nails leading to discoloration, nail plate thickening and onycholysis. It is a very common disease in both podiatric and dermatological practices, accounting for more than 90 percent of toenail infections and at least 50 percent of fingernail infections.1
Onychomycosis occurs more often in our elderly patients.2 It occurs in 10 percent of the general population, 20 percent of individuals 60 years of age and older, and 50 percent of those over 70 years of age. Peripheral vascular disease, immunological disorders and diabetes mellitus correlate with an increased prevalence of nail fungus.2 There are a number of other predisposing factors including male gender, genetic predisposition and presence in other family members, tinea pedis, smoking, nail trauma and hyperhidrosis.
In addition to being a common disease with a suggested increasing prevalence, onychomycosis is both progressive and difficult to manage successfully. One can treat it with topical or systemic agents. The standard of care, especially in moderate to severe disease, is an oral antifungal—either terbinafine (Lamisil, Novartis) or itraconazole (Sporanox, Bristol-Myers Squibb)—as it is more effective. However, more recently topical agents such as tavaborole (Kerydin, PharmaDerm) and efinaconazole (Jublia, Valeant Pharmaceuticals) have become available since penetrance into the nail apparatus may be more effective, either with enhanced penetration through the diseased nail, or subungual delivery under the nail plate.
Our objective is to share personal experience with these new topical antifungals and assess the impact they are having on the management of onychomycosis.
Historically, the majority of our patients used oral drugs (terbinafine or off-label use of fluconazole) for onychomycosis. There were too many drug-drug interactions with itraconazole and its efficacy was not as good. Older patients especially were more suited to fluconazole once a week because they didn’t want to take terbinafine. These were often patients with diabetes on multiple medications or those with peripheral neuropathy and having difficulties cutting their toenails.
Primary care physicians dissuaded some patients from using oral therapy. Indeed, misconceptions about oral treatment are still prevalent in primary care today. We were encouraged to use ciclopirox and had high hopes for the modality. However, cure rates were not very impressive and it left a thick layer on the nail that patients had to remove every week. Occasionally, we might have used ciclopirox in the very mildest cases (less than 20 percent nail involvement) and only then in patients in whom oral drugs were contraindicated or whose disease had recurred following terbinafine treatment.
We had very few options prior to the introduction of the new topical agents. If patients had comorbidities or did not want an oral drug, you did not treat the onychomycosis.
What Is The Impact Of New Topical Agents For Onychomycosis?
More of our patients are now using topical agents since tavaborole and efinaconazole have become available although cost can be a significant influencer. These new topicals are a lot easier and simpler to use, and much more patient-friendly. There is no weekly removal of topical residue so it is more forgiving and less messy. In addition, people are asking for topicals more often.
Tavaborole appears to have similar efficacy to ciclopirox but tavaborole is easier to apply.3 In our experience, results are better with efinaconazole, supporting the published clinical data.4 We have been very impressed with efinaconazole treatment success data (less than 10 percent affected toenail involvement), and discuss with our patients that cure is hard to achieve at 48 weeks. In terms of the “success rate,” we have found about half the patients treated with efinaconazole can expect treatment success.
Topical agents are not effective when the matrix is involved and we don’t use them when there is proximal involvement. When a lot of toenails are involved, treatment can more difficult. As most of these patients also have severe disease, we tend to prefer oral agents. Use of topicals is predominantly for mild to moderate onychomycosis (less than 40 percent of the affected toenail and a nail thickness of less than 3 mm), those patients who don’t want to use a systemic agent, or those with contraindications to oral therapy.
However, in assessing which patients would benefit from topicals, it is so much more than just affected toenail severity. It is important to know many nails are involved, how long have patients had the disease, their past medical history, what topical agents they have used before, and other factors and activities that might affect outcome. Sometimes, the infection starts with the smallest toenails and as a result, you don’t necessarily need an oral drug.
Clinical studies have suggested tavaborole or efinaconazole are less effective in more severe disease, but treatment regimens were relatively short-term and authors have suggested that either a longer treatment regimen or longer follow-up would lead to better results given the time taken for the diseased nail to grow out in these patients.5,6
Recently, a single-center study involving 22 patients with moderately severe onychomycosis (40 to 70 percent of the affected target toenail and up to nine non-target toenails affected) who were treated with daily efinaconazole for 48 weeks showed high mycologic cure rates 24-weeks post-treatment with a corresponding increase in treatment success (50 percent improvement in the target toenail) from 43 to 59 percent.7 These data suggest that our more severe patients might receive more effective treatment with topical agents with a longer treatment course or follow-up. Adherence rates were especially high with only one patient lost to follow-up and there was no evidence of disease recurrence or relapse during the 24-week post-treatment follow-up.
Current Expectations On Topical Treatment Duration And Results
We would normally try a course of topical therapy for at least a year, using photographs to compare how the nail(s) look and making a clinical evaluation every three months. Visual impact is very important both to assess improvement and reassure our patients, especially over the first few months. We get patients to take pictures of their nail(s) on their own phone at regular intervals.
The first milestone is the patient’s three-month post-treatment visit. Although patients should not expect to see too much change at this stage as toenails only grow about 1 mm per month, the follow-up visit helps address any adherence issues associated with a chronic disease. The real litmus test is what the nail looks like in six months. Most patients seem pretty happy with the results by then and we would expect to see improvements at this visit.
If we don’t see a change (we would have marked the proximal infection to be sure), it is important to reevaluate management options. We would not consider switching to an oral therapy before six to nine months of topical use. Non-responders to topical agents probably have thicker nails, more severe disease, more nails involved or more deformed nails (although recent studies with efinaconazole have challenged that view).7 If the disease continues to progress despite topical treatment, we might try adjuvant oral therapy (sometimes weekly fluconazole or terbinafine).
How long we might expect to continue to treat a patient depends on the situation. In a young, healthy patient with fast growing nails and minimal nail involvement, treatment may be less than a year. In the majority of cases, we would recommend treatment for least a year and in some cases two years. Many of the people we see have had onychomycosis for five years or more, which is hard to reverse in less than a year.
We have found the efficacy of topical agents in clinical practice, especially with efinaconazole, is much better than what has been reported in the pivotal clinical studies. Patient selection and possibly variation in assessment techniques may have an impact. Many of the patients in the clinical studies had moderately severe onychomycosis. An expectation of complete cure sets the bar inordinately high in comparison to the earlier studies with oral agents.
Complete cure is not the best marker as there can be some remaining dystrophy, which can go unrecognized as the infection is still present. Mycologic cure is a more important target and an outcome more in line with what we see clinically. Visually, things take a lot longer as the nails grow slowly. The nail will eventually become cured if it has the possibility of doing so.
Patient expectations are always high but we need to be more realistic with them in terms of outcome. For many, a 50 percent improvement will be clinically relevant. If this occurs, there may be more acceptance with treatment. A toenail that looks acceptable in sandals may be a better target. We treat until the nail is normal or the fungus has gone, but there are some cases in which the nail can never be cured/normal.
In patients with longstanding onychomycosis and those not cured following a treatment course, dermatophytomas may develop. As dermatophytoma was an exclusion in clinical trials with topical agents, their likely treatment impact was unknown.8 In addition to improved penetration through the nail plate, experimental research with efinaconazole has suggested effective subungual delivery.9 Subungual delivery may help where onycholysis is present and the nail has lifted off the nail bed as opposed to trying to get the topical medication through the nail. The thick, adherent fungal masses within and under the nail plate that result in dermatophytomas are difficult to treat due to their location in the subungual space, and its surrounding biofilm.
A recent case series involving 19 patients with dermatophytomas showed dramatic clinical improvements with daily use of topical efinaconazole applied on, around and especially under the nail.10 The authors noted 75 percent of dermatophytomas were cleared at or before week 16 with a mean time to resolution of 18 weeks.
Pertinent Considerations With Combination Therapy
Combination therapy does appear to increase cure rates in our experience. Combination therapy is an important consideration in patients with moderate to severe disease, multiple nail involvement or coexisting tinea pedis. In some cases, the topical agent may reach the area of infection better.
In patients with more severe disease, we would consider starting with a systemic and topical treatment for three months (either terbinafine or fluconazole with efinaconazole), and then continuing with the topical. In some cases, we might start with a topical and introduce the oral once we get the culture results.
For those with coexisting tinea pedis, we would also treat their tinea pedis with an appropriate topical antifungal.
Addressing Key Challenges In Treating Onychomycosis With Topicals
Adherence is a key issue with topical antifungals but it is difficult to tell to gauge the level of adherence. In our experience, probably at least half of the patients don’t adhere fully to medication instructions and usage is frequently intermittent. Most patients start out with the best of intentions but applying topical agents only three to four times a week is more typical as people get frustrated, tired or just forget for a variety of reasons.
One reason is that some women want to wear nail polish and if they have onychomycosis, they don’t want people to see their diseased toenails so they may be less likely to want to use a topical agent if it means they can’t use nail polish. Although we have cadaver studies that have shown nail polish may not affect penetration of topical agents, we don’t have any real-world efficacy data.11 Accordingly, we can’t know whether topical modalities would be effective when patients use nail polish. We would prefer patients did not use nail polish or at least use it only on special occasions.
We know some patients have the propensity to develop onychomycosis and relapse and recurrence are still very common. The majority of patients who have been on oral medication alone are usually back to taking oral medications again two years after finishing their first course of oral therapy. For most of these patients, a topical agent can be a realistic option as their onychomycosis is not usually as severe as when they first came in or they may not want to take an oral agent again.
Foot hygiene is very important. Using an antifungal cream/powder in the shoes/socks and other preventative measures to stop tinea pedis should help to prevent recurrence of onychomycosis. For patients in whom we expect a high risk of recurrence, topical therapy once or twice a week as maintenance therapy might be useful, and might be a better option than these patients having to start other therapies” or “combination treatment over again.
What We Would Like To See In Future Trials Of Onychomycosis Therapy
In the short-term, it would be helpful to have efficacy data when we use topical antifungals in conjunction with nail polish although the impact on the appearance of nail polish is a consideration. Trials for topical agents should examine either longer treatment courses or follow-up if we are going to continue to set a high bar and give greater consideration to mycologic cure and relevant treatment outcomes. As we all use combinations of oral and topical agents, and a variety of maintenance strategies, it would be helpful to have more research in this area.
In the future, we might expect to see more effective agents. The biggest unmet clinical need is to have something that cures the disease quicker (three months) or a topical agent one can use once a week. The real challenge is to get a new oral antifungal approved by the Food and Drug Administration that can provide improved efficacy and a reduced risk of side effects in comparison to the currently available oral therapies.
In Conclusion
The introduction of new topical treatments for onychomycosis has afforded us the opportunity to treat more patients effectively. Our experience, especially with efinaconazole, has been better than what researchers have reported in clinical studies. Some of the results have been unexpected and in part explained by the time to achieve cure and the importance of subungual delivery. We wouldn’t normally consider topical agents in more severe onychomycosis but these patients might expect good results with efinaconazole. Dermatophytomas, excluded in the clinical trials, showed dramatic clinical improvement with efinaconazole.10
Dr. Pollak is affiliated with Endeavor Clinical Trials in San Antonio.
Dr. Elewski is a James E. Elder Endowed Professor For Graduate Education in the Department of Dermatology at the University of Alabama at Birmingham School of Medicine in Birmingham, Ala.
Dr. Tosti is a Frederic Brandt Professor in the Department of Dermatology & Cutaneous Surgery at Leonard Miller School of Medicine at the University of Miami.
Dr. Vlahovic is a Clinical Associate Professor at the Temple University School of Podiatric Medicine in Philadelphia.
References
1. Ghannoum MA, Hajjeh RA, Scher R, et al. A large-scale North American study of fungal isolates from nails: the frequency of onychomycosis, fungal distribution, and antifungal susceptibility patterns. J Am Acad Dermatol 2000;43:641–648.
2. Westerberg DP, Voyack MJ. Onychomycosis: current trends in diagnosis and treatment. Am Fam Physician 2013:88(11):762-770.
3. Gupta G, Foley KA, Gupta AK. Tavaborole 5% solution: a novel topical treatment for toenail onychomycosis. Skin Therapy Lett. 2015;20(6):6-9.
4. Elewski BE, Rich P, Pollak R, Pariser DM, Watanabe S, Senda H, Ieda C, Smith K, Pillai R, Ramakrishna T, Olin JT. Efinaconazole 10% solution in the treatment of toenail onychomycosis: Two phase III multicenter, randomized, double-blind studies. J Am Acad Dermatol. 2013;68(4):600-8.
5. Ghannoum M, Isham N, Catalano V. A second look at efficacy criteria for onychomycosis: clinical and mycological cure. Br J Dermatol. 2014;170(1):182-187.
6. Elewski BE. A full ‘cure’ for onychomycosis is not always possible. Arch Dermatol. 1999; 135:852–853.
7. Pollak RA, Ilie C. Long-term follow-up of onychomycosis patients treated with efinaconazole. Poster presented at MauiDerm NP+PA Meeting, Colorado Springs, CO, June 2017.
8. Sullivan AN, Wang C, Cantrell WC, Elewski BE. Successful treatment of dermatophytomas with topical efinaconazole 10% solution. Abstract submitted to Winter Clinical Dermatology Conference 2017.
9. Elewski BE, Pollak RA, Pillai R, Olin JT. Access of efinaconazole topical solution, 10%, to the infection site by spreading through the subungual space. J Drugs Dermatol. 2014;13(11):1394-8.
10. Sullivan AN, Wang C, Cantrell WC, et al. Successful treatment of dermatophytomas with topical efinaconazole 10% solution. Poster presented at Winter Clinical, Hawaii, HI, January 2017.
11. Zeichner JA, Stein Gold L, Korotzer A. Penetration of ((14)C)-efinaconazole topical solution, 10%, does not appear to be influenced by nail polish. J Clin Aesthet Dermatol. 2014;7(9):34-6.
