Age Below 40 Years Is Associated With Human Papillomavirus Vaccination Success for Recalcitrant Warts

Dear Editor:

Cutaneous warts are caused by the human papillomavirus (HPV). They can be treated with various methods, such as cryotherapy, laser therapy, and topical applications¹. However, some patients develop persistent warts that are resistant to conventional management. Previous studies have proposed HPV vaccination as an alternative treatment for recalcitrant warts²,³,⁴,⁵. There are several hypotheses on how HPV vaccination helps eradicate recalcitrant warts. The main hypothesis is that the HPV vaccine has cross-reactivity and stimulates the host’s immune system⁴,⁵ Due to the 6-month long injection course and its cost, it is important to identify the patient group that would benefit the most from HPV vaccination.

Additionally, although the recommended age range for HPV vaccination is 9 to 26 years, a significant number of patients with recalcitrant warts exceed this range. However, it remains unclear whether HPV vaccination is beneficial beyond the age group for which it was originally approved. This study aimed to investigate the clinical characteristics associated with the success of HPV vaccination as a treatment modality for recalcitrant warts.

This retrospective study analyzed patients with cutaneous warts who received the HPV vaccination while undergoing conventional treatment for warts at the SMG-SNU Boramae Medical Center between March 2010 and November 2023. We compared the clinical characteristics associated with treatment success in an HPV-vaccinated population instead of comparing vaccinated and unvaccinated patients because the unvaccinated patients were significantly younger and had less number and smaller size of warts than the HPV-vaccinated patients. Patients who were immunocompromised or vaccinated before wart treatment were excluded. Both 4-valent and 9-valent vaccines were administered. However, cryotherapy was not terminated after the initiation of HPV vaccination because we believed that the combination of cryotherapy with immunomodulating therapies could be better than immunomodulating therapy alone⁶. Cryotherapy was only terminated if the patient firmly requested it due to pain.

The patients were categorized into two groups based on treatment outcomes: complete and incomplete responses. A complete response was achieved when no visible warts were observed, and there was no recurrence for up to one month. Variables including age, sex, number and location of warts, treatment duration, and type of treatment were recorded. This study was approved by the Institutional Review Board (IRB) of the SMG-SNU Boramae Medical Center (IRB No. 30-2024-17), and the requirement for informed consent was waived.

Fisher's exact test was used to compare the complete and incomplete response groups. Cox regression analysis was used to identify factors associated with complete responses. Statistical analyses were conducted using SPSS (version 29.0; IBM Corp., Armonk, NY, USA), with the significance level set at p<0.05.

The study included 60 patients with an average age of 26.4 years (standard deviation, 12.6). The sex distribution was almost equal, and the median duration of treatment before vaccination was 7.7 weeks (Table 1). The complete response group comprised 33 patients (55%). When stratified by vaccine type, 47.1% (16/34) of the 4-valent vaccine and 64.0% (16/25) of the 9-valent vaccine achieved a complete response.

Table 1. Baseline characteristics of the study population (n=60).

Characteristics		Total (n=60)	Complete response (n=33)	Incomplete response (n=27)
Age (yr)		26.4±12.6	23.8±10.3	29.6±14.5
	<40	52	33	21
	≥40	8	2	6
Sex
	Male	32	19	13
	Female	28	14	14
Pre-vaccination treatment period (wk)		7.7 (0–106.5)	7.3 (0–75.9)	9 (0–139.1)
Number of warts
	<10	35	20	15
	≥10	25	13	12
Location of warts
	Subungual	21	10	11
	Hand	28	14	14
	Foot	44	25	19
Previous treatment
	Cryotherapy	47	29	18
	Laser	14	7	7
	Topical 5-FU/salicylic acid	27	14	13
	Intralesional bleomycin	18	12	6
	Oral retinoids	15	8	7

Values are presented as mean±standard deviation or number (minimum–maximum). Among the total of 60 patients, 33 showed a complete response, and 27 showed an incomplete response. None of the above characteristics differed significantly between the complete and incomplete response groups.

FU: fluorouracil.

We analyzed the characteristics of patients who achieved a complete response after receiving HPV vaccination. The median time to complete responses was 18.1 weeks after the first injection (Supplementary Table 1). However, no complete resolution was observed in the incomplete response group despite a median follow-up of 25.1 weeks, with the longest follow-up extending to 106.7 weeks. Most patients received concurrent treatment similar to that administered before vaccination. Cryotherapy was the most common treatment (30/33 patients), followed by topical 5-fluorouracil/salicylic acid. Patients who received cryotherapy as concomitant therapy required a median of four sessions, which took a median of 10.9 weeks after vaccination.

The only significant factor affecting the achievement of complete responses was age ≥40 years, which was less likely to achieve complete responses compared to age <40 years (hazard ratio, 0.236; 95% confidence interval, 0.056–0.992; p=0.049). However, other factors, such as sex, number or location of warts, and type of vaccination, did not show significant differences. According to the survival curves, half of the patients under 40 years old achieved complete responses within 24 weeks. However, in the patients over 40 years old, less than half achieved complete responses (Fig. 1).

Fig. 1. Individuals under the age of 40 showed superior outcomes compared to those aged 40 and above. A 50% cure rate was achieved at 24 weeks for patients under 40. Survival curves were plotted using Cox proportional hazards regression.

The complete response rates of previous studies that used HPV vaccination for recalcitrant warts were 46.7% in a study that utilized the 4-valent vaccine⁴, while those for the 9-valent vaccine were 62.2%⁵. Similar complete response rates were observed. In addition, our study found significant differences in complete response rates based on age, with rates of 59.6% and 25% for those aged ≥ and <40 years, respectively. Previous studies that examined age-related differences showed reduced treatment efficacy in individuals aged 27 and above⁵. However, these studies included only partial responders and were conducted without concurrent conventional treatments, which differ from the results of our study.

We analyzed data from only 60 patients, which might be a relatively large sample size among studies on HPV vaccines and recalcitrant warts⁴,⁵,⁷,⁸, but still may not be sufficient. Furthermore, our study design was retrospective and may not have excluded all confounding factors

In conclusion, our results suggest that HPV vaccination could be an option for patients under 40 years of age with recalcitrant warts, particularly those aged 27–39 years, who are outside the recommended age range for HPV vaccination. The age-related decline of the immune system is accompanied by poor vaccine responses in older people⁹, which may partly explain why our results showed a difference according to age. For patients aged less than 40 years, HPV vaccination could be considered if the warts are resistant to conventional treatments for more than 2 months and waiting until the full vaccination course, as it is less invasive, causes less discomfort to the patient, and can be easily added to existing wart treatments. In contrast, it is difficult to recommend for patients aged 40 years and older who have low response rates despite adjunctive cryotherapy.

SUPPLEMENTARY MATERIAL

Supplementary Table 1

Characteristics of the complete response group