Genital Wart Treatment I. General Principles A) Modern approaches have a much better safety profile than older methods but are still plagued with high recurrence rates and variable success rates. See Table 2. B) Patients have HPV infection in multiple locations and have subclinical lesions. C) The goal of treating noncervical HPV infections is the elimination of obvious or troublesome lesions, not eradication of the virus. D) Success in treating may be increased if the area is soaked with 5 % acetic acid to show the extent of infection, thus facilitating more complete removal of lesions. E) Treating male sexual partners with HPV infection has not changed the treatment failure rate in women with cervical dysplasia (34,35) 1) These findings should not deter the clinician from appropriately examinig and treating HPV infected men. F) The life cycle and transmissibility of HPV should be explained to the patient so steps can be taken to decrease further spread 1) Patients should be informed that they are contagious to sexual partners. 2) Sexual abstinence, monogomous relationsships, and condoms may help decrease the spread of the virus. G) Sources for listed drugs and equipment are shown in Table 3. 1. Lesion classifications are shown in Table 4. H) Based on the literature and the authors experience, cryotherapy, LEEP, Laser, TCA, imiquimod, and podofilox are good treatment choices for perineal lesions. Warts on the anal verge are best treated with cryotherapy or laser, with TCA, imiquimod and simple excision used as alternates. Cryotherapy, podofilox, imiquimod, and TCA are the treatments of choice for penile lesions. I. 5-Fluorouracil (5-FU, Efudex) A) Indications. 1)Use is rapidly declining because of pain and cancer report (see complications) 2) Although commonly used, 5-FU is not currently approved for this use. 3) Useful in treating multiple intravaginal and intraurethral condylomata. B) Precautions / Contraindications. 1) Avoid in pregnancy since its safety has not been established and it can be absorbed through skin and mucosal surfaces. C) Protocols 1) Vaginal a) Patient inserts the 5 % 5-FU cream high in the vagina at bedtime. b) The perineal area must be protected with petroleum ointment or zinc oxide and a pad or tampon placed at the introitus to prevent leakage to unaffected areas. c) One regimen uses 1/3 Ortho applicator (3 ml) every night for 5 nights. d) An alternate regimen uses 1/3 of an applicator once a week for 10 weeks. e) There is less incidence of vulvitis with the latter course of therapy, but this method extends the course of treatment. f) The vulva and vagina should be washed and dried in the morning after treatment. g) If irritation becomes severe, the treatment should be discontinued and alternate therapies used. 2) Vulvar and Perianal a) 5% 5-FU cream can be applied to freshly cleaned and washed lesions once or twice a week for up to 10 weeks. b) Care should be taken to apply a thin coat to the lesion only, and the patient’s hands should be washed thoroughly after use. c) Gloves are recommended if the patient has any hand lesions or experiences adverse reactions to contact with the drug. d) Cover with petroleum ointment or zinc oxide and wash off in the morning or when irritation becomes severe. 3) Distal utrethral lesions a) Use a cotton – tipped applicator to apply cream to the distal urethra 3 times a week for to 4 weeks. b) Alternate apliccation in once a week for 10 weeks c) If dysuria becomes a problem, topical lidocaine can be used. 4) Penile lesions. a) Apply a thin film over the lesion and adjacent skin 3 times per week for 3 to 4 weeks. b) After application, the penis should be wrapped in gauze or placed in a condom for 3 hours to prevent medication spread to nonaffected areas. c) The entire area should be washed to remove the medication 3 hours after application. D) Follow-up. 1 to 2 weeks and end of therapy. E) Complications. 1) Local erosions and a high rate of local irritation. a) Krebs et al found that 8.2 % of women who used vaginal 5-FU developed mucosal ulcerations that healed slowly with conservative therapy. (42). 2) It can be painful when used on the vulva, so adequate pain control may be necessary (topical anesthetics, NSAIDS or hydrocodone). 3) It often takes 6 to 8 weeks for denuded epithelium in the vagina to heal. 4) Common post-treatment symptoms include a watery vaginal discharge, local pain, and bleeding during coitus. 5) One case of non-DES-associated vaginal adenosis with clear cell carcinoma after 5-FU therapy has been reported in the literature. (43) 6) There is no evidence of systemic toxicity with normal use. (13,41) F) Efficacy. 1)Success rates vary, from 73 % to 90 % for vaginal lesions to between 50 % and 75 % for vulvar lesions and 80% for penile lesions. (17,41,44,45) See Table 2. II. Alpha interferon A) Indications. 1) Injection Intralesionally has shown efficacy in the treatment of genital condyloma but is not currently widely used. 2). IM use of alpha interferon is being studied but is not yet approved. 3) Topical Interferons have been shown to be ineffective. B) Precautions / Contraindications. 1) It is contraindicated in pregnancy. 2) It may cause menstrual problems in adolescents. (11) 3) Treatment beyond 3 weeks may cause reversible leukopenia and liver enzyme elevations. C) Protocol. 1) Treatment usually consists of injection of 1 million IUs of alpha –interferon per wart 3 times a week for up to 8 weeks. 2) Using 250,000 IU per lesion twice a week for 6 to 8 weeks has also been reported as effective. 3) An insulin syringe is used to inject the wart at its base or into its substance 4) Inject late in the day to minimize side effects. 5) A maximum of 5 lesions can be treated at a time 6) Repeat courses may be used if > 5 lesions. 7) It can also be injected once at the time of laser therapy to help decrease recurrences. (17, 28, 47) D). Follow-up. 1) Every 2 weeks post-therapy. 2) Resolutions may occur up to 3 weeks after therapy is discontinued. (17,47) E) Complications. 1) The most common side effect in injectable interferons is flu-like symptoms that may last 6 to 8 hours after injection. 2) It is currently an expensive therapy. F) Efficacy 1) There is a 50 % to 63 % success rate with this method. (13, 17, 47) See Table 2. III. Podophyllin A) Indications. 1) It usually comes in a 10 % to 25 % solution in tincture of benzoin. 2) It is best suited for small external lesions. B) Precautions / Contraindications. 1) Not recommended for use in the vagina, urethra, perianal area, or cervix. 2). Use in pregnancy is contraindicated (12, 15) 3) Any biopsies should be done before application to prevent confusing or false positive pathological findings. 4) Repeated application to the mouse cervix produces dysplastic changes, so its use on the uterine cervix is not recommended. (13,49) 5) Systemic reactions also may occur. a) With extensive application, application to mucus membranes, or if left on the skin for long periods of time. b) Reactions include nausea, vomiting, fever, confusion, coma, renal failure, ileus, and leukopenia. (15, 17, 46) C) Protocol. 1) Application of podophyllin in tincture of benzoin by trained personnel once to twice weekly for a maximum of 4 weeks. 2) The solution should be washed off in 1 to 4 hours after the first application 3) Wash off in 4 to 6 hours after subsequent applications if the first is well tolerated. 4) If the lesion has not resolved in 4 weeks, alternative therapies should be considered.(11,17) 5) The solution should be dry before it comes into contact with normal mucosa. (12) D) Follow-up for treatment and until healed. E) Complications 1) Local erosions, ulcerations, and scarring, as well as irritation of adjacent skin. 2) Balanitis and phimosis are risks when podophyllin is used treating men. F) Efficacy. 1) Its success rate ranges from 20 % to 77 % but its recurrence rates may be as high 65 % (17, 13) See Table 2. IV.Podofilox (Condylox) – a purified active component of podophyllin. A) Indications. 1) This purified from is better standardized and safer, and is now indicated for patient application to genital lesions. B) Precautions / Contraindications. 1) Not recommended for use in the vagina, urethra, perianal area, or cervix. 2) Not yet studied for pregnancy. C) Protocol 1) The solution should be applied twice daily for 3 consecutive days, with 4 consecutive days of no therapy each week, for a maximum of 4 weeks. D) Follow-up in 4 weeks and then until healed. E) Efficacy. 1) Success rates vary from 44 % to 88 %. (13,50) See Table 2. V Trichloroacetic and Bichloroacetic Acid A) Indications 1) Used for external and vaginal lesions B) Precaution / Contraindications 1) Quickly inactivated after contact with tissue – toxicity reactions are not a problem. (46) C) Protocol 1) Trichloroacetic acid can be prepared in different strengths. 2) A thin layer of solution is applied only to the wart itself. 3) May use bicarbonate or talc to neutralize any excess acid (12) 4) A 50 % solution is applied with a cotton – tipped applicator or toothpick to the affected area three times a week for a maximum of 4 weeks. 5) An 80 % solution can be applied twice a day for 3 consecutive days each week for a maximum of 4 weeks. (28) 6) Trichloroacetic acid is not sold as a standard preparation and must be compounded at a pharmacy. D) Follow-up every 1 to 3 weeks until healed. E) Complications 1) The depth of penetration of the acid can be difficult to control. 2) Penetration through the dermis can result in slow to heal ulcerations and scar formation. 3) Pain also can be a problem with this therapy. F) Efficacy. 1) The response rates are between 50 % and 81 %, and there is a high rate of recurrence (13) See table 2. VI Imiquimod (Aldara) A) Imiquimod cream is the first of a new class of drugs that act as an immune response modifier. (75) 1)Induces multiple subtypes of interferon-alpha (INF-a) 2) This causes induction of several cytokines including tumor necrosis factor and interleukins. 3) These in turn activate natural killer cells. T-cells, PMN’s, and macrophages increasing antitumor activity. A) Indications 1) Treatment of external genital and perianal condyloma acuminata. 2) Pregnancy Class B. B) Precautions / Contraindications. 1) Not for use on occluded mucous membranes (vagina, cervix) because of absorption. C) Protocol 1) A thin layer of cream is applied and rubbed into the lesion three times a week every other day for up to 16 weeks. Do not occlude. Cotton gauze or underware and acceptable. 2) Wash off after 6 to 8 hours. 3) Cream may be applied to the affected area, not strictly to the lesion itself. 4) Wash hands before and after application. 5) If irritation develops, suspended treatment until resolves. D) Follow-up E) Complications 1) Common side-effects include local reactions such as erythema, itching, skin flaking, and edema. 2) Rare (<5%) side-effects include headache, flu-like symptoms, and myalgias. F) Efficacy. (Product Insert and 76) 1) Overall cure rates of 50-56 %. 2) Imiquimod demonstrates clearance rates of 72-77 % for women and 33-40 % for men and> 50 % wart reduction rates of 85 % and 70 % respectively.

Table 1. Relative Frequency of Location of Condylomata acuminata * MEN   WOMAN     Location          Frequency (Range) Location              Frequency (Range) Prepuce 65%(49-80) Vulvar 85%(77-94) Glans 46%(22-70) Perianal**                  58%(13-85) Urethral 34%(24-45) Vaginal 42%(32-52) Shaft 27%(16-55) Cervix*** 34%(16-64) Scrotal 23%(20-25)     Perianal** 9%(3-15)     Table 2. Comparison of Outpatient Treatment Modalities and Cost. * Treatment Modality Average number of Treatments Succes Rate ** Recurrence< 6 month Average Length of  Study Follow-up Total Cost to Parient *** CO2 Laser  1.3 89% 8% 13.9 months  ----- CO2 Laser + 5FU 1(Laser) 10 to 48 (5-FU) 94% ---- ----- ----- Cryotherapy 1.9 83% 28% 2.7 months  $ 156.50 Cryotherapy+5FU 1 (Cryo): 1(5.FU) 83% ---- ----- $ 165.00 Electrocautery                1.4 93% 24% 3  months   $ 181.00 Interferon Locally9 11 52% 25% 7.8  months   $ 805.00 Imiquimod 30 56% ---- 7     months   $488.00 LEEP  1 90% ---- 8     months $  155.00 Podophylin 4.2 65% 39% 6 months  $ 237.00 Podofilox 10.5 (patient applied) 61% 34% 3.2  months $180.00 Excision 1.1 93%