Original Research

Imiquimod Cream 2.5% and 3.75% Applied Once Daily to Treat  External Genital Warts in Men

Cutis. 2015 October;96(4):277-282

References

1. Weinstock H, Berman S, Cates W. Sexually transmitted infections in American youth: incidence and prevalence estimates, 2000. Perspect Sex Reprod Health. 2004;36:6-10.

2. Dunne EF, Unger ER, Sternberg M, et al. Prevalence of HPV infection among females in the United States. JAMA. 2007;297:813-819.

3. Koutsky L. Epidemiology of genital human papillomavirus infection. Am J Med. 1997;102:3-8.

4. Kjaer SK, Tran TN, Sparen P, et al. The burden of genital warts: a study of nearly 70,000 women from the general female population in the 4 Nordic countries. J Infect Dis. 2007;196:1447-1454.

5. Woodhall S, Ramsey T, Cai C, et al. Estimation of the impact of genital warts on health-related quality of life. Sex Transm Infect. 2008;84:161-166.

6. Mortensen GL, Larsen HK. The quality of life of patients with genital warts: a qualitative study. BMC Public Health. 2010;10:113.

7. Wang KL, Jeng CJ, Yang YC, et al. The psychological impact of illness among women experiencing human papillomavirus-related illness or screening interventions.  J Psychsom Obstet Gynaecol. 2010;31:16-23.

8. Lawrence S, Walzman M, Sheppard S, et al. The psychological impact caused by genital warts: has the Department of Health’s choice of vaccination missed the opportunity to prevent such morbidity? Int J STD AIDS. 2009;20:696-700.

9. Winer RL, Kiviat NB, Hughes JP, et al. Development and duration of human papillomavirus lesions, after initial infection. J Infect Dis. 2005;191:731-738.

10. Centers for Disease Control and Prevention. Human papillomavirus: HPV information for clinicians. Atlanta, GA: Centers for Disease Control and Prevention, US  Department of Health and Human Services; April 2007.

11. Forcier M, Musacchio N. An overview of human papillomavirus infection for the dermatologist: disease, diagnosis, management, and prevention. Dermatol Ther. 2010;23:458-476.

12. Scheinfeld N, Lehman DS. An evidence-based review of medical and surgical treatments of genital warts. Dermatol Online J. 2006;12:5.

13. Aldara [package insert]. Bristol, TN: Graceway  Pharmaceuticals, LLC; 2010.

14. Komericki P, Akkilic-Materna M, Strimitzer T, et al. Efficacy and safety of imiquimod versus podophyllotoxin in the treatment of genital warts. Sex Transm Dis. 2011;38:216-218.

15. Beutner KR, Tyring SK, Trofatter KF Jr, et al. Imiquimod, a patient-applied immune-response modifier for treatment of external genital warts. Antimicrob Agents Chemother. 1998;42:789-794.

16. Beutner KR, Spruance SL, Hougham AJ, et al. Treatment of genital warts with an immune-response modifier (imiquimod). J Am Acad Dermatol. 1998;38:230-239.

17. Edwards L, Ferenczy A, Eron L, et al. Self-administered topical 5% imiquimod cream for external anogenital warts. Arch Dermatol. 1998;134:25-30.

18. Fife KH, Ferenczy A, Douglas JM, et al. Treatment of external genital warts in men using 5% imiquimod cream applied three times a week, once daily, twice daily, or three times a day. Sex Transm Dis. 2001;28:226-231.

19. Garland SM, Waddell R, Mindel A, et al. An open-label phase II pilot study investigating the optimal duration of imiquimod 5% cream for the treatment of external genital warts in women. Int J STD AIDS. 2006;17:448-452.

20. Schofer H, Van Ophoven A, Henke U, et al. Randomized, comparative trial on the sustained efficacy of topical imiquimod 5% cream versus conventional ablative methods in external anogenital warts. Eur J Dermatol. 2006;16:642-648.

21. Arican O, Guneri F, Bilgic K, et al. Topical imiquimod  5% cream in external anogenital warts: a randomized, double-blind, placebo-controlled study. J Dermatol. 2004;31:627-631.

22. Gollnick H, Barasso R, Jappe U, et al. Safety and efficacy of imiquimod 5% cream in the treatment of penile genital warts in uncircumcised men when applied three times weekly or once per day. Int J STD AIDS. 2001;12:22-28.

23. Trofatter KF Jr, Ferenczy A, Fife KH. Increased frequency of dosing of imiquimod 5% cream in the treatment of external genital warts in women. Int J Gynecol Obstet. 2002;76:191-193.

24. Baker DA, Ferris DG, Martens MG, et al. Imiquimod 3.75% cream applied daily to treat anogenital warts: combined results from women in two randomized, placebo-controlled studies [published online ahead of print August 24, 2011]. Infect Dis Obstet Gynecol. 2011;2011:806105.

25. Dinh TH, Sternberg M, Dunne EF, et al. Genital warts among 18- to 59-year-olds in the US, National Health and Nutrition Examination Survey, 1999-2004.  Sex Transm Dis. 2008;35:357-360.

26. Insinga RP, Dasbach EJ, Elbasha EH. Assessing the annual economic burden of preventing and treating anogenital human papillomavirus-related disease in the US: analytic framework and review of the literature. Pharmacoeconomics. 2005;23:1107-1122.

27. Koshiol JE, Laurent SA, Pimenta JM. Rate and predictors of new genital warts claims and genital warts-related healthcare utilization among privately insured patients in the United States. Sex Transm Dis. 2004;31:748-752.

28. Insinga RP, Glass AG, Rush BB. The health care costs of cervical human papillomavirus-related disease. Am J Obstet Gynecol. 2004;191:114-120.

Secondary end points were 75% or more and 50% or more reduction in EGW count, change in EGW count from baseline, and 12-week sustained clearance rate.

Safety

Safety assessments of AEs, both volunteered and elicited, were made throughout the study.

Study Oversight

The study was conducted in accordance with the ethical principles specified in the Declaration of Helsinki and in compliance with the requirements of local regulatory committees. All participants provided written informed consent.

Statistical Analysis

Statistical analysis for intention-to-treat (ITT) imputations was made for missing data points using last observation carried forward (LOCF). Complete clearance rates and partial clearance rates were analyzed using Cochran-Mantel-Haenszel statistics stratified by center and by gender for the overall population analyses. The percentage change in EGW count was analyzed using analysis of covariance.  All statistical analyses were performed using SAS software (version 9.1.3).

Results

Study Population

Study characteristics by treatment group are summarized in the Table. Overall, 447 male participants (225 from study 1 and 222 from study 2) were included in the study. The majority of participants (84.1%) had EGWs on the penile shaft with only 1 affected region in just over half of participants (51.9%). Most participants (70.2%) were 35 years or younger, and approximately half had a baseline EGW count of 7 or less (50.6%). More than 20% of participants had an affected wart surface area greater than 150 mm² at baseline, and in more than 60% of participants, the duration from first diagnosis of EGWs to enrollment in the study was more than 1 year.

Primary Efficacy End Point

Imiquimod cream 3.75% was statistically superior to placebo in study 1 and  study 2 (P=.015 and P=.019, respectively)(Figure) in providing complete clearance of all EGWs (baseline or new) at EOS. Imiquimod cream 2.5% was only statistically superior to placebo in study 2 (P=.034). Importantly, there were a number of participants who did not achieve complete clearance at EOT who continued to improve posttreatment. The percentage of participants treated with imiquimod cream 3.75% and 2.5% who were completely cleared at EOT was 12.0% (14.7% study 1 and 9.1% study 2) and 7.1%  (7.2% study 1 and 7.1% study 2), respectively, compared to complete clearance rates of 18.6% (20.0% study 1  and 17.0% study 2) and 14.3% (13.3% study 1 and  15.3% study 2), respectively, at EOS (ITT population).

Complete clearance rates (defined as the proportion of participants by the end-of-study [EOS] visit with zero external genital warts in all anogenital anatomic areas) in the intention-to-treat (ITT) population (last observation carried forward [LOCF])(A) and per-protocol (PP) population (OC [observed case])(B), including both individual and pooled study data.

In both studies complete clearance rates were significantly higher (P<.019 both studies) with imiquimod cream 3.75% compared with placebo at weeks 10 through 16 (EOS). In study 2, complete clearance rates were significantly higher (P<.049) with imiquimod cream 2.5% compared to placebo from week 14 to week 16 (EOS). Complete clearance rates were highest in participants treated with imiquimod cream 3.75% who had EGWs in the perianal region or on the glans penis (28.6% and 33.3%, respectively); however, the number of participants in both groups was relatively small.

Overall, 18.8% of participants took rest periods. Complete clearance rates were higher in men who took a rest period (26.5% and 27.3% for imiquimod cream 3.75% and 2.5%, respectively), perhaps reflecting a more brisk immunological response. The frequency, duration, and number of dosing days prior to the rest period were similar in the active treatment groups and lower in the placebo group.

There was a tendency for older participants  (ie, >35 years) and those with lower baseline EGW counts (ie, ≤7) to respond better. Participants treated with imiquimod cream 3.75% also tended to respond best to treatment when only 1 anatomic area was affected.

Secondary Efficacy End Points

The proportion of male participants with at least a 75% reduction in EGW count from baseline at EOS was statistically superior with imiquimod 3.75% compared to  placebo in study 1 and study 2 (P=.001 and P=.008, respectively). Statistical superiority also was apparent with imiquimod cream 2.5% versus placebo in study 2 (P=.013). Overall, 20.2%  (18.1% study 1 and 22.4% study 2) and 27.3% (30.5% study 1 and 23.9% study 2) of participants achieved  at least a 75% reduction in wart count at EOS with imiquimod cream 2.5% and 3.75%, respectively (pooled data).

Percentage change in EGW count from baseline at EOS was 35.8% and 24.1% with imiquimod cream 3.75% in study 1 and study 2, respectively, both significantly better than placebo (P=.002 and P=.011, respectively). Change in EGW count following treatment with imiquimod cream 2.5% was only significant in study 2 (P=.001).