**6. Antimitotic therapy**

## **6.1 Bleomycin**

Bleomycin is a chemotherapeutic agent which has an antitumor, antibacterial and antiviral activity which may be related to its ability to bind with deoxyribonucleic acid (DNA), causing bleomycin strand scission and elimination of pyrimidine and purine bases [116]. It selectively affects squamous cell and reticuloendothelial tissue [117]. Bleomycin is not thought to bind directly to HPV [10]. Bleomycin causes acute tissue necrosis that may stimulate an immune response, as evidenced by the fact that it is less effective as a wart treatment in immunosuppressed renal transplant patients [118–121].

Adverse effects include injection pain and burning, erythema, swelling and pain within 24–72 h after injection before a black thrombotic eschar forms. Local complications after periungual injections are nail loss [122] or dystrophy [123]. Reynaud's phenomenon in treated fingers, local pigmentation [124] or urticaria [122], even flagellate hyperpigmentation [125] are reported after.

In a systemic review [126], comparing intralesional bleomycin with placebo, the studies have given conflicting results. Intralesional bleomycin was compared with saline or sesame oil; duration was 6 weeks to 3 months. The RCTs in the review favour I/L Bleomycin, and only one study opined placebo to be more effective. The result of wart clearance was between 18 and 94%, but the study showed clearance rate to be 94%, which was not significantly different from the result (73%) achieved by placebo injections of saline. Concentration of 0.5% bleomycin is more effective than concentration of 0.25% or 1% bleomycin. Pain was experienced by most patients, irrespective of doses. In a study of comparison between intralesional Bleomycin and cryotherapy, 0.1% concentration of bleomycin was used [127]. Greater efficacy in clearing warts was shown with intralesional bleomycin than in cryotherapy. The clearance rates of warts for intralesional bleomycin therapy found were 97%, and in 94.9% of patients, all warts treated with bleomycin were cleared. There was significantly less number of treatment sessions, with a mean of 1.38 in case of bleomycin treatment than the cryotherapy where the mean is 3.08.

### **6.2 Podophyllotoxin**

Podophyllotoxin is a topical antimitotic that is purified from the plant families Coniferae and Berberidaceae (e.g. species of *Juniperus* and *Podophyllum*) or can be synthesised chemically. It is the active agent of podophyllin resin and is available as a 0.5% solution. Podophyllotoxin binds to microtubules and causes mitotic arrest in the metaphase of cell division [128]. Treatment should be limited to no more than 10 cm<sup>2</sup> of wart tissue, and no more than 0.5 mL/day of solution should be given. This is a patient-applied therapy. Podophyllin is a non-standardised unstable plant extract, derived from may apple (*Podophyllum peltatum Linné*), and contains the active agent podophyllotoxin. American *Podophyllum* contains one fourth the amount of podophyllotoxin than Indian *Podophyllum* does. The potency of podophyllin varies considerably between batches. The exact mechanism of action is unknown. Since it tends to work better on mucosal surfaces, it is used primarily to treat genital warts. Little information is available regarding treatment of non-genital warts with this medication. A single topical application of podophyllin cures less than one third of patients with genital warts [129, 130].

It results in necrosis when applied to anogenital warts. Only a trained medical professional can apply it, and it cannot be dispensed to a patient. CDC guidelines for anogenital warts, recommended regimens for External Anogenital Warts (i.e. penis, groin, scrotum, vulva, perineum, external anus and perianus), includes patient-applied therapy with podofilox (podophyllotoxin) 0.5% solution or gel—using a cotton swab or finger. This podofilox solution (using a cotton swab) or gel (using a finger) should be applied to anogenital warts twice daily for 3 consecutive days, followed by 4 days of drug interval. If necessary, it can be repeated, for up to four cycles. The total treated area should not exceed 10 cm<sup>2</sup> , and up to 0.5 ml podofilox should be used per day [131]. If possible initial application should be demonstrated by one healthcare provider for demonstration of proper application and technique and to identify the appropriate warts for treatment. Mild to moderate pain or local irritation might develop after treatment [131].

Podophyllotoxin, the active ingredients of podophyllin, is contraindicated in pregnancy. Though human data not available during application in lactating mother, it is considered as potential toxic. Podophylline, a raw form, is also contraindicated in pregnancy and breastfeeding mother, due to the potential severe myelotoxicity and neurotoxicity in the mother, though no human data available. The American college of Obstetricians and Gynecologists and other sources contraindicated the use of podophyllum agents include the use of podophyllotoxin (podofilox) during pregnancy and in the vagina or cervix at any time [132]. In a randomised comparative study, 60 women with genital warts were treated with either weekly application of 20% podophyllin solution or self-treatment with 0.5% podophyllotoxin cream twice daily for 3 days in weekly intervals. Patients were treated for a maximum of four treatment cycles, and final assessment was carried out after 3 months. Podophyllotoxin cream had a significantly better clearance than podophyllin solution, a primary clearance of was 82% vs 59%. These final clearance decreased to 71% and 48% at the 3-month follow-up, respectively. Total wart clearance was 94% with podophyllotoxin and 74% with podophyllin solution. Podophyllin cream came to as easy to apply and effects significantly better than podophyllin solution. Local side effects were mild to moderate with erythema, and erosion appeared to be higher in the podophyllotoxin group but not so serious to discontinue treatment [133].

**43**

**Table 1.**

*Human Papillomavirus Infection: Management and Treatment*

This treatment uses the patient's own immune system to fight the warts. Some types of immunotherapy only target certain cells of the immune system. Others affect the immune system in general. Because of the cumbersome nature of the conventional procedures and a high risk of recurrence, immunotherapy is becoming more and more popular, especially in the treatment of refractory cutaneous and genital warts. These include various topical, intralesional and systemic agents. There are no well-defined criteria or consensus on when immunotherapy should be tried in a patient with warts. Current indications [134] include the following (**Table 1**).

4.Difficult-to-treat areas—periungual and palmoplantar sites

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

*Various agents used in immunotherapy of warts.*

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

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

**7. Immunotherapy**

1.Recalcitrant warts

2.Recurrent warts

3.Extensive warts

**7.1 Imiquimod**
