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Original Study

Efficacy and Safety of Imiquimod Versus Podophyllotoxin in the Treatment of Anogenital Warts

Komericki, Peter MD*; Akkilic-Materna, Merve MD*; Strimitzer, Tanja PhD; Aberer, Werner MD*

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Sexually Transmitted Diseases: March 2011 - Volume 38 - Issue 3 - p 216-218
doi: 10.1097/OLQ.0b013e3181f68ebb
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Genital warts are the visible manifestation of infection by human papillomaviruses (HPV), mostly by HPV 6 and 11.1 HPV infection is the most common sexually transmitted disease. The estimated prevalence rate in the US population is 15%, and 1 million new cases of genital warts are diagnosed every year.2 Treatment options for genital warts are numerous, well-established, and effective. Evidence of efficacy in the treatment is drawn from randomized blind-controlled trials, prospective studies, and retrospective cohort studies, but more head-to-head studies need to be done.3 Failure of treatment and recurrence after initial clearance are seen with all treatments.4

The current study compares the efficacy and safety of self-administered podophyllotoxin and imiquimod for the treatment of untreated external anogenital warts. Both agents are used as first-line treatment for genital HPV-associated lesions in Austria.

We want to emphasize that our work was not funded by any drug manufacturer.


Consecutive patients who presented with anogenital warts over a period of 2 years were included in the randomized, open-label trial with a statistical power of 0.8, an α error of 0.05 and a relevant difference to detect of 0.15. Patients were referred to the outpatient clinics for sexually transmitted diseases (STD) at the Department of Environmental Dermatology and Venereology of the Medical University of Graz, Austria. Inclusion criteria were the presence of never treated anogenital warts. Exclusion criteria were age below 18 years, lack of informed consent, known immunosupression, pregnancy, breast-feeding, involvement of the anal canal, or severe disease requiring surgery.

Eligible patients who consented to participate underwent an assessment which included registration of the site of disease (anal, genital, anogenital) and the severity of lesions (mild = wart area 0–100mm2; moderate 100–200mm2; severe = >200mm2). Both, imiquimod (Aldara 5% cream, 3 mol/L Health Care, Loughborough/Leicestershire, GB) and podophyllotoxin (Condylox 0.5% solution, Nycomed Austria, Linz, Austria) were approved in Austria for the treatment of anogenital warts and both were first line treatments (Guidelines of the Working Group for STD, Austrian Society for Dermatology and Venereology, Allocation to treatment groups was done according to a ranking, which was created by block randomization. Each block contained 4 items (2× imiquimod and 2× podophyllotoxin) to assure a balanced design with equal group sizes. Imiquimod was used 3 times per week until the warts completely cleared, or for a maximum period of 16 weeks. Podophyllotoxin was used 2 times on 3 consecutive days per week until the warts completely cleared, or for a maximum period of 4 weeks.

Serology testing for HIV and syphilis and a urethral smear test (combined with a cervical smear test in women) were performed to screen the patients for other STD. Urethral and cervical specimens were analyzed under a microscope of wet preparation and Gram-stained slides, by cultures for Neisseria gonorrhoeae, Ureaplasma urealyticum, Mycoplasma hominis, and by nucleic acid amplification tests for N. gonorrhoeae and Chlamydia trachomatis.

Efficacy (primary endpoint) was assessed at the end of treatment, 5 weeks after the start of podophyllotoxin and 16 weeks after the start of imiquimod. Two groups were created: (a) patients whose warts had completely cleared and (b) patients without complete clearance.

Side effects (secondary endpoint) were assessed at each check up, 2 weeks after the start and at the end of podophyllotoxin treatment; and 4, 8, 12, and 16 weeks after the start of imiquimod therapy. Patients were assigned to one of the following categories: (a) no side effects, (b) erythema/inflammation, (c) erosions, (d) erythema/inflammation plus erosions. Just the most severe adverse event was once scored for each patient irrespective of the date and number of presentations.

The statistical package SAS 9.2 was used for statistical analysis. For contingency tables, Fisher exact test was used to test for statistical significance.


One patient refused the participation, as he wished an immediate surgical intervention.

In total, 51 patients were randomized to one of the treatment groups (26 individuals to podophyllotoxin and 25 to imiquimod). Six patients were lost to follow-up, 5 in the imiquimod, and 1 in the podophyllotoxin group.

Forty-five patients, 7 women and 35 men of whom 5 were circumcised, completed the treatment and were eligible for evaluation. Patients' mean age was 30.3 years (30.0 years in the podophyllotoxin group, and 30.8 years in the imiquimod group) and the age range 18 to 54 years. The distribution of genders and wart characteristics (primary localization and severity) were similar among treatment groups. Allocation to treatment-arm (imiquimod vs. podophyllotoxin), sex, severity, and location of lesions are shown in Table 1. Statistically, there were no differences among treatment groups (sex: P = 0.43, severity: P = 1, location: P = 0.91).

Distribution of Sex, Severity, and Location of Lesions Among Treatment Groups

Smear tests performed in 36 patients revealed 2 positive results for C. trachomatis, 13 for U. urealyticum, 1 for M. hominis, 2 for U. urealyticum together with M. hominis, and 1 for T. vaginalis. Nine patients refused a smear test. Infections were treated according to STD guidelines. Serology testing for HIV and syphilis were negative in all cases.

In the intend-to-treat analysis, the rates of clearance of baseline warts among treatment groups were 72% (18/25) in the podophyllotoxin group and 75% (15/20) in the imiquimod group (Table 2). Statistically, clearance rates were identical (P = 1). A separate analysis in respect of clearance rate and gender was not performed regarding the small number of women.

Complete Clearance Rates of Treatments

The most common local skin reaction in either treatment group was erythema/inflammation (E/I) (37.8%, Table 3). At the time of check-up, no side effects were seen in 4 individuals of the podophyllotoxin group. The strongest reactions (E/I plus erosions) were more often seen in the imiquimod group (40% vs. 24%). The differences in side effects among treatment groups did not achieve statistical significance (P = 0.24).

Side Effects of Treatment


This is the first report of a direct comparison of podophyllotoxin and imiquimod, whereas previous studies have been focused on the evaluation of these agents against placebo.

Podophyllin resin (an extract of the root of Podophyllum sp), in alcoholic solution was first described as effective treatment for genital warts in 1942.5 Podophyllotoxin has been shown to be the most important active component and is superior to podophyllin in terms of purity, stability, lack of systemic toxicity, and efficacy.6–8 Podophyllotoxin inhibits the proliferation of human skin keratinocytes and cures genital warts by inhibiting proliferation of HPV-infected cells. Placebo-controlled trials with podophyllotoxin showed clinical cure rates between 37% and 83%.9–11

Imiquimod 5% cream is a topical immune response modifier, which had shown antiviral and antitumorous properties by inducing the production of cytokines (interleukins, interferon, TNFα) as well as by stimulating dentritic cells and lymphocytes. FDA approval of imiquimod for the treatment of external genital warts in immunocompetent individuals was issued in 1997. Patient applied 5% imiquimod cream was more effective compared to 1% cream and had a favorable safety profile.12 The optimal application schedule of imiquimod 5% cream for external anogenital warts was 3 times per week.13 In placebo controlled trials, imiquimod treatment was associated with complete clearance rates of 37%, 50%, and 67%.14–16

In a meta-analysis of the efficacy of imiquimod 5% and podophyllotoxin 0.5%, clinical cure rates of 50.34% and 56.41%, respectively, were obtained. The difference did not achieve statistical significance. Authors concluded that imiquimod and podophyllotoxin exert similar curative effects on condylomata acuminata. However, they drew attention to an important limitation of their analysis, namely the absence of any direct comparison of imiquimod and podophyllotoxin in the past.17

This study confirms the mathematical data showing that imiquimod 5% cream and podophyllotoxin 0.5% exert an identical beneficial effect on anogenital warts.

The primary objective of complete clearance was achieved in 75% of patients with imiquimod 5% and in 72% with podophyllotoxin 0.5%; the outcome was identical in statistical terms (P = 1). Clearance rates for imiquimod were better than previously reported and in the upper range for podophyllotoxin.

In view of the small patient population, differences in clearance rates and sex, localization, and severity were not calculated. The higher proportion of men compared to women was likely result of the fact, that women consult their gynecologists first in case of genitourinary complaints.

The secondary objective was the assessment of side effects. We focused on objective parameters alone, which were graded as follows: no visible side effect, E/I, erosions, and erosions in conjunction with E/I. No side effects were seen in 4 patients of the podophyllotoxin group, whereas all patients in the imiquimod group had at least E/I. The most severe adverse event of erosions in conjunction with E/I was more often seen in imiquimod users, but even these effects were rated harmless and acceptable. However, the differences in side effects between treatment groups were statistically not significant. Our data were in contrast to observations that podophyllotoxin had more serious adverse effects compared to imiquimod.17

A disadvantage of imiquimod compared to podophyllotoxin was the long duration of treatment (4 months vs. 4 weeks). Patients' compliance might have been poorer as a result thereof. Six of a total of 51 patients were lost to follow-up, 5 in the imiquimod group. This might be due to poor compliance, although the actual reasons remained unclear. Intolerable adverse reactions and receipt of care outside the trial could be reasons. Patients were contacted by mail and telephone without success. In clinical trials, patients with genital warts not infrequently default from follow-up.18 This fact may well favor the use of podophyllotoxin, which needs to be used for a shorter period of time.

Study Limitations

The small sample size could have limited the power to detect smaller differences in efficacy and side effects between the 2 agents. A potential bias might result from lack of blinding patients and clinicians as to the treatment assignment. A bias might be introduced by more frequent and prolonged assessment of side effects for the imiquimod group. Regarding the gender distribution in our trial, there were limitations in the generalization to females.

Finally, the direct comparison of imiquimod and podophyllotoxin showed equal efficacy of the substances in the treatment of anogenital warts, as confirmed indirectly by the meta-analysis.

In contrast to the meta-analysis, stronger adverse reactions were seen in the imiquimod group, even if the difference did not achieve statistical significance.

Both substances represent effective and safe agents for the management of untreated anogenital warts in immunocompetent individuals.


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