11/01/2022
Background
Topical ionic contraviral therapy (ICVT) with digoxin and furosemide inhibits the potassium influx on which DNA viruses rely for replication. Therefore, ICVT was hypothesized to be a potential novel treatment for cutaneous warts.
Objectives
To assess the clinical efficacy, safety and tolerability of ICVT in adults with cutaneous warts. The secondary objective was to gain insight into the underlying working mechanism of ICVT.
Methods
Treatment with ICVT was assessed for efficacy, safety and tolerability in a single‐ centre, randomized, double‐blind, placebo‐controlled phase IIA trial. Eighty adult patients with at least two cutaneous warts (plantar or common) were randomized to one of four treatments: digoxin + furosemide (0·125%), digoxin (0·125%), furosemide (0·125%) or placebo. The gel was administered once daily for 42 consecutive days. Predefined statistical analysis was performed with a mixed‐model ancova. The trial was registered at ClinicalTrials.gov with number NCT02333643.
Results
Wart size and human papillomavirus (HPV) load reduction was achieved in all active treatment groups. A statistically significant reduction in wart diameter of all treated warts was shown in the digoxin + furosemide treatment group vs. placebo (−3·0 mm, 95% confidence interval −4·9 to −1·1, P = 0·002). There was a statistically significant reduction in the HPV load of all treated warts in the digoxin + furosemide group vs. placebo (−94%, 95% confidence interval −100 to −19, P = 0·03). With wart size reduction, histologically and immunohistochemically defined viral characteristics disappeared from partial and total responding warts.
Conclusions
This study demonstrates the proof of concept for the efficacy of topical ICVT in adults with cutaneous warts.
Cutaneous warts, or verrucae, are a common benign skin condition with an estimated prevalence of 3–13% in the general population in the Western world.1 Most people are affected by cutaneous warts, either plantar warts (located on the foot soles) or common warts (mostly located on the hands or dorsal feet), at some point in their life.1, 2, 3, 4
Although cutaneous warts are benign and usually resolve spontaneously,5 they cause both physical and psychosocial discomfort.6 Many patients use a variety of wart‐removing products.6, 7, 8 Efficacy rates of common treatments are approximately 39% for cryotherapy, 24% for salicylic acid and 46% for monochloroacetic acid, whereas spontaneous regression rates are around 16%.7, 9, 10, 11 As current treatments such as cryotherapy and monochloroacetic acid often have side‐effects (e.g. pain, erythema and burning sensation)12 and low efficacy rates, there is a need for therapies with a greater efficacy and minimal side‐effects.13, 14, 15
Cutaneous warts are caused by the human papillomavirus (HPV). The great majority (> 80%) of verrucae in the general population are related to HPVs 1, 2, 27 and 57.16, 17, 18, 19, 20, 21 It is well known that papillomaviruses are dependent of the milieu of the infected host cell for proliferation.22, 23 More specifically, it has been shown that DNA viruses, such as HPV, rely on potassium ion influx for replication.24 The cardiac glycoside digoxin and loop diuretic furosemide both inhibit K+ influx by interacting with the cell‐membrane ion cotransporters Na+/K+‐ATPase and Na‐K‐Cl. These two compounds may therefore be valuable for the treatment of HPV‐induced diseases, such as cutaneous warts. In 2006, an in vitro study found that the inhibitory effect on DNA replication was most potent when digoxin and furosemide were combined. This new approach with two well‐known, established drugs, described as ionic contraviral therapy (ICVT), is suggested to be most effective via local application.25
A previous phase I/II open‐label study recently demonstrated the safety and efficacy of ICVT in a group of 12 healthy patients with common warts.26 The aim of the current proof‐of‐concept study was to assess the clinical efficacy, safety and tolerability of ICVT in adults with cutaneous warts in a single‐centre, randomized, double‐blind, placebo‐controlled phase IIA trial. The secondary objective was to gain insight into the underlying working mechanism of ICVT.
