Genital warts (GW) are sexually transmitted disease caused by human papillomaviruses (HPV). Usually they are asymptomatic but, depending on the size and location, may be painful or itchy. If left untreated, visible genital warts can resolve on their own, remain unchanged, or increase in size or number. Before the treatment is started, the physician should fully assess the entire lower genital tract, including performing a Pap smear, to rule out the presence of a cervical lesion (carcinoma).
There are many modalities for treating genital warts, depending on the morphology, number and distribution of warts and patient preference. However, none of them provide 100% chance of clearance or 0% chance of recurrence. Also, there is no clear evidence that any one treatment is superior to the others.
Therapy may be applied by the patient or by the provider. A treatment response is usually seen within 3months.
The US latest (2010) guidelines on GW treatment recommend the following options:
External genital warts
- Cryotherapy with liquid nitrogen or cryoprobe or
- Podophyllin resin 10-25% in a compound tincture of benzoin or
- Trichloroacetic acid (TCA) or bichloracetic acid (BCA) 80-90% or
- Surgical removal by tangential scissor excision, tangential shave excision, curettage, or electrosurgery.
Alternative regimens include treatment options that might be associated with more side effects and/or less data on efficacy. These include:
- intralesional interferon
- photodynamic therapy
- topical cidofovir.
- Cryotherapy with liquid nitrogen or
- TCA or BCA 80-90%
Urethral meatus warts
- Cryotherapy with liquid nitrogen or
- Podophyllin 10-25% in compound tincture of benzoin
- Cryotherapy with liquid nitrogen or
- TCA or BCA 80-90% or
- Surgical removal
Because all available treatments have shortcomings, some clinics employ combination therapy (simultaneous use of two or more modalities on the same wart at the same time). Data are limited regarding the efficacy or risk of complications associated with use of such combinations.
Clearance and recurrence rates for individual treatments in the published literature are shown in the following table (according to the UK National Guideline on the Management of Ano-genital Warts, 2007).
|Treatment||Clearance rates (%)|
|LEEP (loop electrical excision procedure)||<90||-||-|
|TCCA (trichloracetic acid)|
*Studies using more than one treatment strength have been grouped together.
It is important to mention that these studies are not comparable in design, methods and endpoints.
Genital warts. In: Sexually transmitted diseases treatment guidelines, 2010. Centers for Disease Control and Prevention (CDC). MMWR Recomm Rep 2010 Dec 17;59(RR-12):70-4.
United Kingdom national guideline on the management of anogenital warts. London (UK): British Association for Sexual Health and HIV (BASHH); 2007. 18 p. Clinical Effectiveness Group, British Association for Sexual Health and HIV (BASHH).
PODOPHYLLIN and PODOPHYLLOTOXIN (PODOFILOX, CONDYLOX)
Podophyllin is a resin derived from the rhizome (underground root) of the mayapple (Podophyllum peltatum), a plant that grows wild in eastern North America. Podophyllin was the first topical treatment ever applied on GW. It is also used nowadays as a 10-25 % suspension in tincture of benzoin (physician applied). Podophyllin is an antimitotic agent that interferes with viral activity by inducing local tissue necrosis.
Applied directly to each genital wart, it is left for six hours and then washed off. This process may be repeated one time per week, for up to 6 weeks or until the warts are gone. Once applied to each wart it should be allowed to air-dry before the treated area comes into contact with clothing; over application or failure to air dry can result in local irritation caused by spread of the compound to adjacent areas. The preparation should be thoroughly washed off 1–4 hours after application to reduce local irritation. In rare cases the use of podophyllin is associated with side effects due to systemic absorbtion and toxicity. To avoid such effects, application should be limited to <0.5 mL of podophyllin or an area of <10 cm2 of warts per session. Also, the area to which treatment is administered should not contain any open lesions or wounds. In very rare cases liver dysfunction, bone marrow suppression, nausea, diarrhea or constipation, abdominal pain, neurological impairment or even psychosis may occur. The safety of podophyllin during pregnancy has not been established.
The resin formula is made a few hours before the appointment. It is unstable so it cannot be stored easily; therefore it must be applied fresh and later disposed in a biohazard bin since it is poisonous.
In terms of relative effectiveness, the study results are conflicting. A randomized study in 60 patients with once weekly podophyllin showed initial complete clearance of 93 percent versus 77 percent for surgical excision. Recurrence rates were 18% for surgical excision and 43% for podophyllin at 3 months, 22% and 56% at 6 months, 26% and 56% at 9 months, 29% and 65% at 12 months (Jensen SL, 1985). In another study (Khawaja HT, 1989) at 6 weeks scissor excision completely cleared the warts in 89% compared with 79 % treated with podophyllin. Recurrence was 19% in the surgery group, compared to 60% in the podophyllin group.
A randomized controlled trial in 97 patients evaluated the efficacy of intralesional interferon 2b and podophyllin versus podophyllin alone for the therapy of anogenital warts. The conclusion was that intralesional administration of interferon seemed to enhance the effect of topical podophyllin (Douglas JM, 1990).
Another study has shown that in a cohort of 409 individuals with new or recurrent warts, randomly allocated to one of 5 treatments on a weekly basis, single therapy with either trichloracetic acid or podophyllin 25% resulted in longer time to wart clearance, and more persistent warts (Sherrard J, 2007).
Thus, the disadvantages to the use of podophyllin include unstandardized preparation, side effects, lower effectiveness, failure to induce lasting remission. It may also contain the mutagenic flavonoid compounds quercetin and kaempherol. Podophyllin preparations vary greatly in their active component and contaminant concentrations.
Podophyllotoxin is the main active ingredient of podophyllin resin that has been purified and prepared to a well standardised concentration. Also known as Podofilox or Condylox (brand name), it is available as cream, gel, or solution preparations that can be self applied by the patient. Because of its purity and ease of use, podophyllotoxin is to be preferred over podophyllin.
Podofilox solution is applied with a cotton swab, or podofilox gel with a finger, to visible genital warts twice a day for 3 days, followed by 4 days of no therapy. This one week cycle of treatment may be repeated until there is no visible wart tissue or for a maximum of 4 cycles. If there is incomplete response after four treatment cycles, it is recommended to discontinue treatment and consider alternative treatment. No evidence suggests that more frequent application will increase efficacy. However, additional applications do increase the rate of local adverse reactions and systemic absorption. The total wart area treated should not exceed 10 cm2, and the total volume of podofilox should be limited to 0.5 mL per day. If possible, the health-care provider should apply the initial treatment to demonstrate the proper application technique and identify which warts should be treated. Mild to moderate pain or local irritation might develop after treatment. The safety of podofilox during pregnancy has not been established.
Eight randomized controlled trials (RCTs), involving 1035 patients compared the efficacy of podophyllotoxin versus placebo (Syed TA, 1995; Greenberg MD, 1991; Beutner KR, 1989; Kirby P, 1990; Tyring S, 1998; von Krogh G, 1992; 1994; Syed TA, 1994). All found that, within 16 weeks of treatment, podophyllotoxin was more effective for clearance than placebo (RRs of clearance v placebo ranged between 2.0 [95% CI 0.9 to 4.3] and 48.0 [95% CI 3 to 773]). RCTs of 0.5% cream or solution found recurrence rates ranging from 4% to 33%. One RCT (57 patients) of 0.5% podophyllotoxin solution as prophylaxis against recurrence of external genital warts found fewer recurrences among people taking placebo.
When comparing podophyllotoxin versus podophyllin, five RCTs found no significant difference in wart clearance (RR values for podophyllin vs podophyllotoxin ranging between 0.7 [95% CI 0.4 to 1.1] (Hellberg D, 1995) and 1.7 [95% CI 0.9 to 3.2]) (Lassus A, 1984). One of these RCTs used a 2% podophyllin solution in a limited study of self-treatment for penile warts, and found no significant difference in clearance between podophyllotoxin and podophyllin (RR for podophyllin v podophyllotoxin 0.6, 95% CI 0.3 to 1.3) (White DJ, 1997). The sixth RCT (358 immunocompetent men and women with genital warts for 3 months or less, 276 [77%] completed) compared podophyllotoxin (self-treatment with 0.5% solution or 0.15% cream twice daily for 3 days with 4 days off) versus podophyllin (25% applied twice weekly at a clinic) (Lacey CJ, 2003). Both treatments were given until warts were cleared, up to a maximum of 4 weeks. The RCT found that podophyllotoxin solution, but not podophyllotoxin cream, significantly increased complete remission of warts at 4 weeks compared with podophyllin (intention to treat analysis: OR 1.92, 95% CI 1.13 to 3.27 for solution; OR 1.17, 95 % CI 0.69 to 2.00 for cream). It found no significant difference between treatments in recurrence of warts at 12 weeks among those with initial clearance (74 people analysed: 15/33 [45%] with podophyllotoxin solution v 12/22 [54%] with podophyllotoxin cream v 5/19 [26%] with podophyllin; P reported as not significant). High withdrawal, and the potential for selection bias among returning people, limit the reliability of these results.
One study comparing podophyllotoxin with topical interferon has found that topical interferon significantly increased wart clearance at 4 weeks after treatment compared with podophyllotoxin (18/20 [90%] with topical interferon v 12/20 [60%] with podophyllotoxin; P = 0.0285) (Syed TA, 1995).
Possible side effects reported with podophyllotoxin are local inflammation or irritation, erosion, burning, pain, itching, and more rarely dyspareunia, bleeding, scarring, and insomnia.
RCTs examined the efficacy of podophyllotoxin solutions more often than cream preparations, but cream or gel preparations may be easier to apply than solutions. This and other differences may cause variable efficacy.
Podophyllotoxin does not contain the mutagenic flavonoid compounds quercetin and kaempherol, which are contained in podophyllin resin preparations.
Reutner KR, Conant MA, Friedman-Kien AE, et al. Patient-applied podofilox for treatment of genital warts. Lancet 1989;i:831–834
Bonnez W, Elswick RK Jr, Bailey-Farchione A, Hallahan D, Bell R, Isenberg R, Stoler MH, Reichman RC. Efficacy and safety of 0.5% podofilox solution in the treatment and suppression of anogenital warts. Am J Med. 1994;96:420-5.
W Buck H Jr. Warts (genital). Clin Evid (Online). 2010 Aug 13;2010. pii: 1602.
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Greenberg MD, Rutledge LH, Reid R, et al. A double-blind, randomized trial of 0.5% podofilox and placebo for the treatment of genital warts in women. Obstet Gynecol1991;77:735–739
Hellberg D, Svarrer T, Nilsson S, et al. Self-treatment of female external genital warts with 0.5% podophyllotoxin cream (Condyline) vs weekly applications of 20% podophyllin solution. Int J STD AIDS1995;6:257–261
Jensen SL, Comparison of podophyllin application with simple surgical excision in clearance and recurrence of perianal condylomata acuminata. Lancet. 1985;2(8465):1146-8.
Khawaja HT. Podophyllin versus scissor excision in the treatment of perianal condylomata acuminata: a prospective study. Br J Surg. 1989;76:1067-8.
Kirby P, Dunne King D, Corey L. Double-blind randomized clinical trial of self-administered podofilox solution versus vehicle in the treatment of genital warts. Am J Med1990;88:465–469.
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Lacey CJ, Goodall RL, Tennvail GR, et al., for the Perstorp Pharma Genital Warts Clinical Trial Group. Randomised controlled trial and economic evaluation of podophyllotoxin solution, podophyllotoxin cream, and podophyllin in the treatment of genital warts. Sex Transm Infect2003;79:270–275.
Sherrard J, Riddell L. Comparison of the effectiveness of commonly used clinic-based treatments for external genital warts. Int J STD AIDS. 2007 Jun;18(6):365-8.
Management of genital warts in women with human leukocyte interferon-alpha vs. podophyllotoxin in cream: a placebo-controlled, double-blind, comparative study. J Mol Med (Berl). 1995 May;73(5):255-8.
Tyring S, Edwards L, Cherry LK, Ramsdell WM, Kotner S, Greenberg MD, Vance JC, Barnum G, Dromgoole SH, Killey FP, Toter T. Safety and efficacy of 0.5% podofilox gel in the treatment of anogenital warts. Arch Dermatol. 1998;134:33-8.
Von Krogh G. Topical self-treatment of penile warts with 0.5% podophyllotoxin in ethanol for four or five days. Sex Transm Dis1987;14:135–140.
Von Krogh G. Penile condylomata acuminata: an experimental model for evaluation of topical self-treatment with 0.5–1.0% ethanolic preparations of podophyllotoxin for three days. Sex Transm Dis1981;8:179–186
White, DJ, Billingham C, Chapman S, et al. Podophyllin 0.5% or 2.0% v podophyllotoxin 0.5% for self treatment of penile warts: a double blind randomised study. Genitourin Med1997;73:184–187.
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