• Ivan Bristow

The return of Nitric Acid for Verrucae


Recently, we have seen an interest here in the UK of a new product for the treatment of plantar warts called Verrutop®. Any innovation always is welcome, particularly for the management of warts. As always one must ask about the effectiveness and safety of any new treatment so, in this blog article, I have collated the available published papers to look at this topical product and its effectiveness in the treatment of plantar warts.




New Light through old windows?


The product originates from Europe, where much of the research has emanated. Labelled as a Nitric-Zinc Complex Solution (NZCS), the product marketed as Verrutop® in the United Kingdom is a combination of things that have been previously used in wart treatments – nitric acid (65%), metallic salts (zinc and copper) and organic acids (8.5% each). Nitric acid has a long history in the treatment of stubborn warts and indeed if you still have some of the older podiatry textbooks you may find it written about as P J Read did in 1950 (1), but it disappeared in the 1960s as a mainstream wart treatment.




Copper is a metal that is still being touted as a home treatment for warts. Just search YouTube and you can see the “one penny” treatment. Rubbing your warts with an old penny (older ones have a higher copper content) and it is purported to eradicate stubborn lesions. There is an element of truth in this – copper oxide has been shown to have some effects against the HPV virus, but its effectiveness, when used in this way, is not known – although one could say it is very cheap.

Zinc is also something much discussed in warts treatment, and something I have covered on this blog before (READ HERE). The other constituents include oxalic acid (a reducing agent) which incidentally, can be found in rhubarb. The high concentration of oxalic acid particularly in the leaves is what makes them poisonous. Lactic acid and acetic acid (vinegar) are other ingredients. The combination of these products makes sense as a “chemical cocktail” that has the potential to be anti-viral.



Research

Back in 2012, the first publication appeared investigating this new product (2). It was not a patient trial but purely to see if there was any suggestion it could have any effect on the human papillomavirus. Using ten excised human warts, from each one, 9 samples were taken and subjected to cryotherapy, the test product (NZCS) or remained untouched as a control. The idea was to examine the cells after treatment and to see if HPV DNA could be extracted afterwards (suggesting whether it may affect wart viability). The work showed that after three treatments with both cryotherapy and NZCS wart samples showed a reduction in hyperkeratosis and destruction of infected cell nuclei. Additionally, the NZCS was able to destroy viral DNA in 60% of cases, to an undetectable level. Cryotherapy had no effect on viral DNA destruction. This suggested the product was able to reduce the viral DNA load and so potentially could be used to treat warts.

Subsequently, a clinical study was undertaken as a “proof-of-concept” – could it be safely used in wart treatment? Four clinics in Italy recruited subjects with palmar, plantar, periungual, and anogenital warts to test the safety and effectiveness of the product (3). 37 patients were treated at 2 weekly intervals with up to 2 or 3 treatments. The headline complete resolution rate was an impressive 90% with no significant adverse reactions (2). The important point to note here was that only 2 of these warts were plantar warts. So, from a podiatric point of view, this work did not really offer evidence of effectiveness, despite the eye-catching resolution rate.

In 2018, a poster was presented at the European Academy of Dermatology meeting in France. This was a summary of the experience of the product in treating 210 patients. In this study, up to six applications were used fortnightly in patients with hand and foot warts. The complete clearance rate was 77% (4). Unfortunately, the breakdown of data failed to report how many of these lesions were plantar warts. Additionally, the age of the patients was not reported. As is well known in wart studies, younger populations can skew results as the likelihood of spontaneous regression is always a possibility.

A Spanish study latterly was conducted on children using the product and published in the journal Dermatologic Therapy in 2019. The cohort of 12 children (average age of 9 [age range 4-16] and wart duration ranging from 6 to 40 months) were treated fortnightly with NZCS, for an unspecified number of treatments (“until resolution occurred”) (5). The average number of treatments was given as 6 applications. The complete clearance rate was just under 84% of treated warts. The authors report that only five of these were plantar warts but do not make clear how many resolved as they only mention 5 out of 7, "palmoplantar" warts resolved. Also, some patients received up to 9 treatments.

The Journal of Dermatology published other Spanish research which included 25 plantar lesions treated in an uncontrolled study design (6). The clearance rate for these plantar lesions was 88%. An impressive figure but the authors report a randomized controlled trial is required to confirm this finding.

The most recent work (“the SILVER study”) took a different approach and asked dermatologists in Italy to retrospectively review their patient cases treated with NZCS and report their findings (7). A total of 83 patients were retrospectively identified with “difficult to treat warts”. Interestingly, they reported the average duration of these to be under a year. As one patient’s data was incomplete a total of 82 patients were analyzed. In this work, only 22% of patients had complete clearance of palmoplantar warts but the treatment was well tolerated. The analysis also highlighted, as with most wart treatments, that the treatment of plantar warts using the NZCS was less effective.


Discussion

Looking at this as a new topical product it is good to see there is published research out there investigating its use. Podiatrists are always looking at new ways to treat warts, particularly those on the plantar surface. Despite all this, the question remains how effective is this for plantar verrucae with studies suggesting a wide range between 22% - 88% effectiveness? With many wart treatments, the formidable thicker skin barrier of the sole is a major hindrance to some treatment modalities. To answer this question, it is going to need more specific research as most of the data is broadly pertains to the skin and anogenital warts making it difficult to draw solid conclusions. In addition, one paper containing dermatologist-reviewed results suggesting reduced effectiveness on plantar lesions.

One study investigated recurrence rates for warts successfully treated with NZCS - 100 patients were followed up to assess how many warts returned during a three and six-month window. The rate of recurrence at three months was rather high at 29% with a further 5% recurring after six months. This may give some insight into longer-term effectiveness but this data was only from patients with anogenital warts (8).

The safety of the product is demonstrated through much of this work, but practical points are missing. From my own experience of using this, the application of the product onto a lesion does cause a strong transient stinging sensation when applied in some patients. So how will this product fit into the podiatry market alongside other current treatments such as salicylic acid and Swift microwave?


Firstly, the product itself is designed for clinical, rather than home use. It is supplied in a pack containing four treatments, each one in an individual glass vial which is applied via a supplied glass tube to the wart under treatment. The cost price of the verrutop® (4 treatments) to the podiatrist is around £40 (or £60 for a patient requiring six treatments) before any mark-up is added. With the patient returning fortnightly (according to studies) for six treatments or more and adding an appointment or treatment fee, the price of treatment will be much higher than for salicylic acid making it a more expensive option, close to microwave treatment, for example. With microwave, there is no need for any patient intervention between treatments, and application times are short. Moreover, verrutop® patients are required to wipe the surface of the lesion daily with alcohol to allow the treatment optimal conditions in which to work. For some patients, this may be difficult or easily forgotten in their daily routine. Consequently, practitioners may have to look carefully as to where this fits into their business model.


References

1. Read PJ, Kemp C. Verruca Pedis: Methods of Treatment. London: Actinic Press; 1950.

2. Viennet C, Gheit T, Muret P, Aubin F, Cabou J, Marchal A, et al. Assessment of the efficacy of a new formulation for plantar wart mummification: new experimental design and human papillomavirus identification. Clin Exp Dermatol. 2013;38(1):85-8.

3. Cusini M, Micali G, Lacarrubba F, Puviani M, Barcella A, Milani M. Efficacy and tolerability of nitric-zinc complex in the treatment of external genital warts and "difficult-to-treat" warts: a "proof of concept", prospective, multicentre, open study. G Ital Dermatol Venereol. 2015;150(6):643-8.

4. Galloni C, Balice Y, Facchetti M, Marchetti S, Motta L, Pisacane D. Efficacy and tolerability assessment of a new medical device containing a nitric-zinc complex to treat palmar, plantar and periungual warts: experience with 210 patients [poster]. 27th European Academy of Dermatology; 12th - 16th September 2018; Paris, France2018.

5. Giacaman A, Granger C, Aladren S, Bauzá A, Alomar Torrens B, Riutort Mercant M, et al. Use of Topical Nitric-Zinc Complex Solution to Treat Palmoplantar and Periungual Warts in a Pediatric Population. Dermatology and therapy. 2019;9(4):755-60.

6. Rozas-Muñoz E, Mir-Bonafé J, Piquero-Casals J. Refractory warts successfully treated with a nitric–zinc complex solution. The Journal of Dermatology. 2019;46(7):e250-e1.

7. Puviani M, Manfredini M, Eisendle K. The SILVER study. Efficacy of topical nitric-zinc complex solution in the treatment of resistant warts: A postmarketing evaluation. Dermatol Ther. 2019;32(4):e12940.

8. Ciccarese G, Drago F, Granger C, Parodi A. Efficacy Assessment of a Topically Applied Nitric-Zinc Complex Solution for the Treatment of External Ano-genital Warts in 100 Patients. Dermatology and therapy. 2019;9(2):327-35.









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