Monotherapy for Toenail Onychomycosis

A Systematic Review and Network Meta-analysis

A.K. Gupta; K.A. Foley; R.R. Mays; N.H. Shear; V. Piguet

Disclosures

The British Journal of Dermatology. 2020;182(2):287-299. 

In This Article

Discussion

This review set out to compare monotherapy (oral, topical and devices) and combination therapies for toenail onychomycosis. We were able to evaluate only oral and topical monotherapies for the outcomes mycological cure and adverse events. Oral and topical treatments demonstrated significantly greater ORs of achieving mycological cure compared with placebo. Continuous terbinafine 250 mg and continuous itraconazole 200 mg showed significantly greater ORs of attaining mycological cure compared with topical treatments. Pulse regimens of terbinafine and itraconazole, and fluconazole were not significantly different from topical treatments. Lastly, there was no difference in the ORs of mycological cure among topical treatments. Quality of evidence was mostly moderate to high.

The odds of experiencing adverse events with any oral or topical treatment were not significantly different from each other. Oral and topical treatments showed statistically similar ORs of experiencing adverse events compared with placebo. The exception to this was adverse events with efinaconazole vs. placebo; a possible explanation for this is that trials reported the majority of events to be application-site reactions related to treatment[33] whereas data available for other treatments included all adverse events, related and unrelated to treatment. Quality of evidence was variable, ranging from very low to high.

SUCRA rankings seem to depict a succinct summary of the efficacy of treatments that clinicians could refer to, but have the potential to be misleading. Rankings need to be interpreted with caution and, within the context of the main results of a NMA, that is the relative treatment effects, as well as the quality of evidence. A treatment may rank favourably, yet low quality of evidence due to concerns with risk of bias, inconsistency and/or imprecision may bring into question the confidence one can have in that favourable ranking.[50]

SUCRA rankings for mycological cure follow closely with treatment effects and the quality of evidence is respectable (moderate to high). Continuous terbinafine and continuous itraconazole have the highest rankings, and the odds of cure were greater with both than with all topical treatments. SUCRA rankings for topical treatments are similar and there were no differences in the odds of cure between topical treatments. For adverse events placebo and tavaborole 5% solution are placed at the top of SUCRA rankings with the least risk for adverse events. SUCRA rankings for the remaining treatments are lower and similar. However, we cannot have confidence in these rankings based on the quality of evidence. Although the odds of experiencing an adverse event were similar across all treatments, the quality of the evidence was low or very low for half of the comparisons, all of which comprised oral treatments. RCTs of oral antifungals for onychomycosis are generally older and, thus, less rigorously reported than recent topical antifungal trials. Additionally, some regimens of oral treatment are used off-label and rigorous data are not available.

In the years following regulatory approval for oral antifungals, reports documenting adverse events with oral treatments have been published and updates to prescribing information have been issued.[51,52] Concerns with drug–drug interactions, hepatotoxicity and, in the case of itraconazole, cardiac events need to weighed against the possible efficacy of oral treatments. Clinicians and patients may prefer the trade-off between decreased efficacy and fewer systemic adverse events understood to occur with topical treatment.

Publication bias may be present as funnel plots for mycological cure and adverse events of treatment vs. placebo are not symmetrical (Figure S7; see Supporting information). Multiple treatments are plotted which may account for this. It appears that there may be bias for continuous terbinafine for mycological cure and for fluconazole for adverse events. Adjusted funnel plots of the NMA for mycological cure and adverse events show fairly good symmetry and provide confidence that publication bias is not distorting results.

We were unable to construct a meaningful network for complete cure, treatment success and QoL. Very few studies report complete cure and treatment success (≤ 10% nail involvement plus mycological cure). The utility of complete cure as a clinical outcome has been discussed in the literature[53] and led to this review's inclusion of treatment success as an outcome of interest. Due to the nature of the disease and possible nail trauma, it is not always possible for onychomycosis treatment to produce a 100% clear nail. Treatment success has been reported in more recent trials[32–34] and may be a clinical outcome that future studies consider including. QoL in patients with onychomycosis is emerging in the literature through post-marketing studies[8,54,55] and has yet to be addressed in depth in RCTs of treatments; the focus on efficacy and safety for regulatory approval may supersede efforts to assess QoL. It is also worth mentioning that in order to ensure as best we can that fungal organisms have been eradicated, mycological cure is defined as negative microscopy and culture; not all studies use both methods to define cure and thus were not included in our analysis.

The number of trials for each comparison in our networks was variable and often low (e.g. 1–2 trials per comparison). Direct comparisons for oral treatments were available; however, head-to-head trials for topical treatments have not been performed. Particularly for adverse events, the quality of trial data was left wanting. A lack of published RCTs for combination therapies and device-based therapies (e.g. laser or photodynamic therapy) prevented us from comparing these treatments with oral and topical monotherapy. Awareness of the importance of high-quality trials to support claims of efficacy for onychomycosis treatment has grown[56] and perhaps in the future, the networks presented here will be expanded upon.

Nevertheless, evidence suggests that oral and topical treatments for toenail onychomycosis are effective in producing mycological cure. The risk of adverse events is similar across treatments with a caveat for clinicians to consult product inserts for warnings and precautions and choose the treatment that best suits their patients' needs. Efficacy rates for oral and topical treatments in general are lower than desired and there is a need for more effective therapy. As technological advances in topical formulations come to fruition and further investigation into device and combination therapy takes place, an improvement in cure rates and patients' lives may be realized.

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