Intralesional Acyclovir Versus Intralesional Zinc Sulphate in the Treatment of Plantar Warts

Viral warts represent benign epidermal proliferations associated with human papillomavirus (HPV) infection. HPV is a double-stranded DNA virus with more than 150 identified types, several of which have a predilection for cutaneous tissues and can produce distinct clinical forms of warts. Transmission occurs through direct skin-to-skin contact, indirect contact with contaminated surfaces, or autoinoculation, as when a wart is scratched or picked and virus is carried to a new site.

Cutaneous warts occur worldwide, with an estimated overall population prevalence of roughly 10%, rising to 10-20% among school-aged children. Although warts may develop at any age, incidence climbs through childhood and peaks between 12 and 16 years. Most lesions are asymptomatic, but they are not without consequence: warts can produce cosmetic disfigurement and psychosocial distress, and those on weight-bearing surfaces such as the plantar skin can become painful with walking or pressure. The principal clinical types are common, plantar, plane, filiform, and genital warts.

Plantar warts, the focus of the present study, arise on the sole and are most commonly attributed to HPV types 1, 2, 4, 27 and 57. Because of the constant pressure exerted by weight-bearing, these lesions tend to grow inward rather than outward and are often covered by a thick overlying callus that can mask the lesion and delay diagnosis; adjacent warts may also coalesce into a mosaic pattern. Unlike many other cutaneous warts, plantar warts are frequently symptomatic, producing a sharp, well-localized pain on walking or standing that can meaningfully impair mobility and daily activities. Clinically, they are distinguished from corns and calluses by the presence of pinpoint black dots, corresponding to thrombosed dermal capillaries, and by interruption of the normal skin lines across the lesion.

Several therapeutic modalities are available for cutaneous warts, including destructive methods such as salicylic acid, cryotherapy, silver nitrate, electrosurgery and pulsed-dye laser, antiproliferative agents such as formaldehyde, vitamin D3, bleomycin, 5-fluorouracil, podophyllin and podophyllotoxin, topical immunological agents such as imiquimod ; However, treatment remains challenging because of variable efficacy, prolonged treatment courses, recurrence and adverse effects. No single treatment option is considered gold standard.

Intralesional therapies are an emerging and effective approach for treating recalcitrant warts. Several immunotherapeutic agents for warts including vitamin D3; tuberculin purified protein derivative (PPD); Candida antigen (Candida); the measles, mumps, rubella (MMR) vaccine, BCG, zinc sulphate and antivirals such as acyclovir have demonstrated variable complete response rates in randomized controlled trials. Unlike various other treatment options, immunotherapeutic approaches upregulate the immune system to recognize and destroy the lesions at both the target site and distant locations.

Acyclovir, a synthetic purine nucleoside analogue, is active against herpes simplex virus (HSV) and varicella-zoster virus (VZV) through a selective activation pathway: viral thymidine kinase first converts the drug to its monophosphate form, after which host-cell enzymes complete its conversion to the active triphosphate metabolite. This triphosphate form competitively blocks viral DNA polymerase and, once incorporated into the elongating viral DNA strand, halts further chain extension, thereby arresting viral DNA synthesis.

Acyclovir is considered an evolving treatment option for warts; however, its mechanism of action against HPV is not fully understood. In a recent randomized controlled trial, intralesional acyclovir (70 mg/ml) was injected at a dose of 0.1 ml using an insulin syringe into each of the largest three warts (total 0.3 ml per session), repeated every 2 weeks until complete clearance or for a maximum of five sessions, resulting in a complete response rate of 37.5%.

The therapeutic effect of zinc sulphate in warts is thought to reflect a combination of direct local cytotoxicity and immune stimulation. Following intralesional injection, it triggers a localized inflammatory cascade in which eosinophils arrive first, followed sequentially by lymphocytes and fibroblasts, which may help drive immune-mediated clearance of HPV-infected keratinocytes. Zinc also contributes to immune regulation by supporting leukocyte and natural killer cell function. However, the precise mechanism by which intralesional zinc sulphate promotes HPV clearance remains incompletely understood.

Zinc sulfate has been investigated as an effective intralesional immunotherapy treatment for warts. A recent randomized controlled study evaluated intralesional 2% zinc sulphate in patients with common, plantar, and plane warts. Zinc sulphate was prepared by dissolving 2 g in 100 ml sterile distilled water and autoclaving at 95°C for 20 minutes. A dose of 0.1 ml was injected into the largest wart until blanching or bleb formation, with treatment repeated for up to six sessions. Complete response was achieved in 68.6% of patients, while complete clearance of the target wart was observed in 74.3% of cases.

Although both agents have demonstrated promising efficacy in the treatment of cutaneous warts, so far, there is no direct comparative study evaluating intralesional acyclovir versus intralesional zinc sulphate. Therefore, the present study aims to provide a direct head to head comparison of the efficacy and safety of intralesional acyclovir versus intralesional zinc sulphate in the treatment of patients with plantar warts.