**7.1 Imiquimod**

Imiquimod is a non-nucleoside heterocyclic amine which acts as an immune response modifier that may stimulate cytokines, including interferon-α, interleukin-1, interleukin-6, tumour necrosis factor-α, granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor [135]. In a quantitative systemic review of published randomised control trials, six RCTs were evaluated, and all six studies were conducted in the sitting of home administration


*Courtesy of Prof Devinder M Thappa and Minu J Chiramel [134].*

### **Table 1.**

*Various agents used in immunotherapy of warts.*

after initial professional examination and advice wart locations are genital, both in males and females. Five of the studies are on immunocompetent patients and one study on HIV-positive patients; 90% of the study population are male. Imiquimod was used as 5% cream in 4 trials and 2% cream in one trial, with complete clearance achieved in 51% in imiquimod group but only 6% patients in placebo group. The number needed to treat (NNT) was 2.2 (95% confidence interval 2.0–2.6). At least 50% reduction in wart area occurred in 72% of patients treated with Imiquimod 5% cream and 20% in placebo treated group. The number needed to treat was 1.9 (1.7–2.2). Warts were completely cured and did not recur in 37% (31% to 43%) of patients treated with imiquimod 5%, and 4% (2% to 6%) of patients treated with placebo. The NNT was 3.0 (2.5 to 3.8). Fewer patients were cured with 1% imiquimod in two trials, and for this concentration the NNT was 9.5 (5.9 to 25). Imiquimod 5% cream was significantly more effective than imiquimod 1% cream for complete wart clearance [136]. Common adverse events were localised itching, erythema, burning and erosion or excoriation, there was rarely any withdrawal from study due to these adverse effects. In HIV infected patients with warts, at least 50% reduction of wart area was seen in 38%, and in placebo it was 14%. Adverse events were similar to non-HIV group [137]. It is found to be effective and safe in children and there are reports of safe use in pregnancy [138, 139]. Disadvantages of using imiquimod 5% cream were the high cost and the length of average treatment (9.5 weeks).

### **7.2** *Mycobacterium w*

*Mycobacterium indicus pranii* or *Mycobacterium w* is rapid growing nontubercular mycobacteria, which has been found to induce a strong pro-inflammatory response while injected intralesionally. There is a prominent delayed hypersensitivity response, leading to clearance of warts both at the site of injection and distally [140]. The response varied by 54–93% in cutaneous warts and 89% in genital warts [140–143]. It is administered in two ways—either with an intradermal sensitising dose or without it. In the first method, a sensitising dose of 0.1 ml is administered intradermally in the deltoid region followed by 2–4 weekly intralesional injections in few warts (maximum 0.1 ml in each sitting) for up to 10 sittings. In the latter, the sensitization dose is missed, and direct intralesional injections are started [140, 141]. Mycobacterium *w* vaccine came as equally efficacious in treatment of refractory extragenital warts in comparison with cryotherapy and Imiquimod, 5%,. Mw vaccine has an added advantage of clearance of distant warts and reduction of viral load [144, 145]. The reported side effects include pain, nodularity, ulceration, scarring at the site of injection, flu-like symptoms, fever and lymphadenopathy [143]. Paraesthesia on the limb distal to the site of injection has also been reported [146].

### **7.3** *Bacillus* **Calmette-Guérin vaccine**

The delayed hypersensitivity response against the antigen is the key to clinical response against warts, same as that of the Mw vaccine. It increases the serum levels of IL-12 and decreases the level of IL-4 [147]. One to three doses are administered 1 month apart. In cutaneous warts (common, plantar, and plane warts), there was a resolution rate of 39.7% [148]. Topically applied BCG paste (weekly for 6 weeks) has also been found to be effective in children with common warts and plane warts with 65% resolution [149], and usually there are no side effects. However, another report in India showed a high incidence of flu-like symptoms precluding further doses in 57% of patients, making one question its safety in tuberculosis endemic countries like India [150].

**45**

lesions with minimum side effects.

Interferon has been shown to be active against HPV both in vitro and in vivo, to protect murine cells against infection with bovine papillomaviruses and to eliminate extrachromosomal viral DNA from infected cells [164, 165]. In a systematic meta-analysis, the rate of complete response in locally used interferon was 44.4% in comparison to placebo, 16.1%. The complete response rate of systemically used interferon as compared to placebo for treating genital warts had no perceivable discrepancy, for systemically used interferon 27.4% and placebo 26.4%. Both groups

**7.5 Interferons**

*Human Papillomavirus Infection: Management and Treatment*

**7.4 MMR vaccine***, Candida, Trichophyton and tuberculin* **antigens**

Various types of vaccines and antigens were tried for wart management. Measles, mumps and rubella (MMR) viral vaccine accelerates the clearance of virus and viral infected cells by stimulation of cell-mediated and humoral immunity [151]. In this double-blind RCT, MMR vaccine was tried for three injections in 2-week interval with normal saline as control; 75% of patients had complete clearance, and another 16.6% had more than 50% clearance. There were no side effects, and in 6-month follow-up, there was no relapse [151]. In another study of MMR vaccine, 81.4% of patients had complete clearance; another 10% had partial clearance, in comparison to 27.5% and 15% with saline control [152]. A preliminary, open-label (PPD: purified protein derivative) study to investigate the effectiveness of the tuberculin antigen in the treatment of recalcitrant warts, taking advantage of the vaccination schedule in their country was designed. Three consecutive intralesional tuberculin (5TU PPD RT23-tween 80 solution) injections with 3-week intervals into each target wart, depending on the tuberculin reactivity, were performed. Injections of 0.3, 0.2 and 0.1 mL of antigen were administered to patients with indurations of 5–9, 10–15 and > 15 mm, respectively. Five patients (29.4%) demonstrated complete clearance, five (29.4%) had partial and five (29.4%) minimal response. Some patients showed complete clearance of untreated facial warts also. Patients with initial PPD test site in duration less than 10 mm had no or minimal response [153]. Mumps and *Candida* antigen injection in paediatric age group with recalcitrant warts had 47% complete resolution, and 13% had partial resolution. Injections were given in three weekly intervals, and an average of 3.87 injections was given. Patients with initial high response to skin antigen test shows excellent result [154]. Injection with mumps, *Candida* or *Trichophyton* antigen, alone or in combination, is given in 3-week interval, up to 10 injections. In patients who have completed the study, 50% had complete clearance, and the other 50% had 75–90% clearance. Local erythema and oedema were the only side effects, in 30% of patients. Patients who had complete clearance had clearance also in their distant verruca lesions [155]. *Candida albicans* intralesional immunotherapy in single also came as safe, well tolerated and suitable for multiple warts of hand and fingers, plantar warts and recalcitrant warts, even in non-injected warts [156]. In a randomised, single blinded, placebo-controlled large study of mumps, *Candida* and *Trichophyton* antigen, with or without interferon α 2b, 41% of patients with antigen alone, 57% antigen and interferon and 9% in only interferon had complete clearance in comparison to 19% only in the normal saline group [157]. The combination of mumps, *Candida* and *Trichophyton* also came to be effective as 74% of patients responded to test antigen had complete clearance with significant number also showing resolution of untreated distant warts [158]. Response of other studies with *Candida* antigen varied as 72% [159], 74% [160], 85% [161], 56% [162] and 87% [163], indicating antigen therapy in wart is a good hope for target and distant wart

*DOI: http://dx.doi.org/10.5772/intechopen.92397*
