Onychomycosis: Does Cure Equate to Treatment Success?
May 2016 | Volume 15 | Issue 5 | Original Article | 626 | Copyright © May 2016
Boni E. Elewski MD,a Aditya K. Gupta MD PhD FRCPC,b Ted Rosen MD,c Bryan D. Caldwell DPM,d David M. Pariser MD,e Leon H. Kircik MD,f Neal Bhatia MD,g and Antonella Tosti MDh
aUniversity of Alabama at Birmingham School of Medicine, Birmingham, AL
bUniversity of Toronto, Toronto, Canada
cBaylor College of Medicine, Houston, TX
dKent State University College of Podiatric Medicine, Independence, OH
eVirginia Clinical Research, Norfolk, VA
fIndiana University School of Medicine, Indianapolis, IN, Physicians Skin Care, PLLC, Louisville, KY, Icahn School of Medicine at Mount Sinai, New York, NY
gTherapeutics Clinical Research, San Diego, CA
hDepartment of Dermatology & Cutaneous Surgery, Leonard Miller School of Medicine, University of Miami, FL
BACKGROUND: There is no general agreement as to what constitutes cure or treatment success in onychomycosis. Regulatory guidelines differ in the United States and Europe, and outcomes reported in clinical trials do not consistently report secondary endpoints.
METHODS: We reviewed definitions of onychomycosis cure to develop a less stringent and more practical approach to assess improvement and treatment success.
RESULTS: Complete cure (totally clear nail and mycologic cure) remains an important regulatory standard. Mycologic cure (negative fungal culture and negative potassium hydroxide) is the only consistently reported outcome in clinical trials, however the potential for discrepancies between microscopy and culture can be problematic. We propose a more practical approach to assessing improvement in infected nails that relies on both physician and patient input in a similar fashion to other skin diseases.
CONCLUSIONS: Treatment success should be based on both physician and patient assessment of improvement in the affected toenails and negative fungal culture. J Drugs Dermatol.
Despite a number of discussions on the topic, there remains no agreement on practical criteria defining resolution of onychomycosis.1,2 Many of the clinical data reported in the literature use a combination of mycologic cure (negative fungal culture and negative potassium hydroxide [KOH]), clinical cure (with 80%-100% clearing of the nail plate), or complete cure (a combination of mycologic and clinical cure, usually comprising a completely normal-appearing nail plate) as the primary and secondary end points for defining success of therapeutic intervention.
The definition of complete cure differs slightly between regulatory agencies; with the US Food and Drug Administration (FDA) requiring a completely clear nail and the EU authorities requiring only a 90% clearing of the nail plate.2 In addition, regulatory guidelines and clinical studies base complete cure on the progress of a single affected target toenail (the great toenail). However, in clinical practice it is common for a number of toenails to be affected, with patients and physicians evaluating the potentially different responses of all toenails. This point is illustrated by a recent study with terbinafine where significant, but expected due to nail length, differences were found in clinical improvement between the great toenail and all other
toenails, suggesting efficacy should be based on all involved onychomycotic toenails.3
Complete cure data from clinical trials may be misleading in that it is highly unlikely to see complete nail clearance in the majority of patients immediately after completion of therapy. Efficacy assessments are often based on final evaluations at 48 (end of therapy) to 52 (4-week follow-up) weeks, but a toenail may not grow fully for up to 78 weeks.4,5 For some patients this timeframe may be longer; toenail growth can be influenced by age, gender and comorbidities. The rate of linear nail growth decreases by 50% during a normal life span,5 while concomitant conditions and certain medications may also cause either an increase or decrease in nail growth.1,6 As a result, the demographics of patients achieving complete cure in clinical trials may not reflect that seen in clinical practice if either longer treatment courses or longer follow-up were possible. In addition, it is important for both clinician and patient to realize that cure may not result in a normal looking nail. While it is the patient’s expectation to get the nail back looking like it once did, it is the physician’s expectation of eradicating the mycological burden; as a result, endpoints could be different.