HUMAN PAPILLOMAVIRUS (HPV) infection is now one of the most common sexually transmitted diseases in the United States, and the increasing incidence is a considerable global health concern. Although the efficacy of imiquimod for treatment of external anogenital warts due to HPV has been confirmed, 1 whether topical imiquimod is appropriate for certain subgroups is an important question.
It is estimated that approximately 20 million sexually active adults are currently infected with HPV and that 5.5 million new cases occur each year. 2 The spectrum of HPV infection ranges from subclinical to clinical disease states. Low-oncogenic-risk HPV subtypes 6 and 11 typically present as genital warts, 3 while high-,oncogenic-risk HPV subtypes 16 and 18 are often associated with anogenital tract malignancies. 4
The presence of genital warts can have a significant psychological effect. Emotional stress involves concern about transmission of HPV to partners, the risk of cancer, and recurrence of warts. 5 To minimize the likelihood that warts will return after initial clearance, patients can be treated with imiquimod 5% cream, a recommended patient-applied treatment for external genital warts, which has a lower rate of recurrence than other ablative or cytodestructive treatments. 6 Imiquimod is an immune response modifier that clears external genital warts by stimulating innate and cell-mediated immune pathways to eradicate HPV-infected cells. 7
A clinical study has shown that topical application of imiquimod to genital warts results in increased production of a number of cytokines, including interferon (IFN)-α, a key cytokine involved in defense mechanisms against viral infection. 7 Increased levels of messenger RNA for IFN-γ, a mediator of the cell-mediated immune pathway, were also observed. 7 Imiquimod treatment also stimulates HPV-specific T cells that are cytotoxic to HPV-infected cells, resulting in a decrease in wart size and ultimately complete clearance. It has been proposed that these specific cytotoxic T lymphocytes may provide long-term immunity to HPV infection. 8
The safety and efficacy of imiquimod were confirmed in a randomized, double-blind, vehicle-controlled trial conducted in the United States and Canada. 1 Complete clearance of external genital and perianal warts was observed in 50% of patients (intent-to-treat [ITT] analysis) who applied imiquimod 3 times a week for up to 16 weeks. 1 Imiquimod treatment was well-tolerated by patients; mild to moderate erythema was the most frequently observed local skin reaction. 1
As physicians have a choice regarding the optimal genital wart treatment for each patient, it is important to know if topical imiquimod 5% cream is more appropriate in certain subgroups of patients. The objective of this study, conducted as part of the above randomized, double-blind, vehicle-controlled study, was to determine if patient demographic variables, such as gender, initial wart size, duration of current outbreak of warts, previous wart treatment, and tobacco use, affect imiquimod's efficacy in the treatment of external genital and perianal warts.
Immunocompetent patients diagnosed with external genital or perianal warts were included in the study. All patients were at least 18 years of age and were required to have a minimum of two and no more than 50 warts. The inclusion criteria for this study was the same as that for the concurrent double-blind, vehicle-controlled study by Edwards et al. 1
At the initial clinic visit, baseline target warts were measured and photographed and their exact location recorded on a diagram. Patients were randomized to receive either imiquimod 5% cream or vehicle cream and were instructed on the correct method of cream application. All subjects wore the cream 3 times a week for 8 ± 2 hours during their normal sleeping hours. Patients were required to refrain from sexual contact while the cream was on the skin.
During the treatment period, patients returned to the clinic at the end of weeks 1 and 2 and then every 2 weeks for up to 16 weeks. At each visit, warts were measured and photographed, and local skin reactions and adverse reactions were documented.
Fisher exact test was used to compare the efficacy of imiquimod and vehicle for each subgroup examined. In order to detect statistical significance, each separate Fisher exact test P value was compared to an alpha level of 0.05 divided by 12. The relative benefit, defined as the imiquimod clearance rate divided by the vehicle clearance rate, was calculated for each subgroup.
Of the 209 patients enrolled in this study, 86 (41%) were female and 123 (59%) were male. After randomization, 109 patients were included in the imiquimod-treated group and 100 in the vehicle-treated group. The demographic characteristics of the patients in the two treatment groups are shown in Table 1. There were no significant differences between the two groups in terms of gender, age, race, height, weight, smoking habits, or extent and duration of disease. For female patients, the majority of warts were vulvar (90%) or perianal (49%), and for male patients warts were mainly located on the penis (82%).
The overall efficacy of imiquimod 5% cream in comparison with vehicle in this study has been previously published by Edwards et al. 1 In brief, in an ITT analysis, 50% (54/109) of patients treated with imiquimod 5% cream experienced complete clearance, compared with 11% (11/100) of those treated with vehicle cream (P < 0.0001). 1
In this data analysis, the efficacy of imiquimod in comparison with vehicle cream was analyzed in relation to patients’ demographic characteristics (Table 2). When the results were examined on the basis of gender, imiquimod was significantly more effective than vehicle cream for male and female patients (P < 0.0001, for both males and females). Complete clearance was reported in 72% of females treated with imiquimod, versus 20% in the vehicle-treated group. Among the male patients, the warts of 33% were cleared in the imiquimod-treated group, compared with 5% in the vehicle-treated group. The relative benefit of imiquimod (the clearance rate with imiquimod, divided by the clearance rate with vehicle) versus vehicle was 3.6 for female patients, indicating that females treated with imiquimod were 3.6 times more likely to have the warts clear than were those treated with vehicle. The relative benefit of imiquimod in comparison with vehicle was 6.7 for male patients (Table 2).
The results were examined on the basis of baseline wart area, which varied greatly between patients, ranging from 7 to 5525 mm2. Analysis of the results revealed that imiquimod was significantly superior to vehicle in the clearance of all warts treated, independent of baseline wart area (Figure 1).
The efficacy of imiquimod compared with vehicle was also analyzed in relation to the duration of the current outbreak of warts. Imiquimod was significantly more effective than vehicle for patients whose warts had been present for 6 months or less (P < 0.0001), as well as those whose warts had been present for longer than 6 months (P < 0.0001) (Figure 2). The relative benefit of imiquimod for patients with warts for longer than 6 months was 9.6 (Table 2), indicating that patients’ warts were 9.6 times more likely to clear if treated with imiquimod rather than vehicle.
Approximately two thirds of patients (141/209) had previously undergone genital wart treatments, most commonly with cryotherapy (27%), podophyllin (23%), and TCA (15%). The efficacy of imiquimod for patients who had previously undergone therapy and for those who had not was similar, and in both groups of patients imiquimod was statistically more effective than vehicle (Figure 3). The relative benefit of imiquimod compared with vehicle was also similar for the two subgroups (Table 2).
Imiquimod therapy was effective in the treatment of genital warts for patients who smoked tobacco and those who did not. A significant difference in clearance rates between imiquimod and vehicle was reported for both nonsmokers (P = 0.003) and smokers (P < 0.0001) (Figure 4).
This data analysis showed that topical imiquimod 5% cream was effective for the treatment of external genital and perianal warts, independent of gender, initial wart size, duration of current wart outbreak, previous therapies, or smoking habits. The data confirmed that imiquimod is an appropriate treatment for each of the patient subgroups.
We observed that the efficacy of imiquimod compared to vehicle was significant in both the female and male subgroups; however, a higher proportion of females (72%) than males (33%) reported total clearance of their warts. This may be due to differences in the location of warts, as the vulva, the most common location of genital warts in females, is less keratinized than the penile shaft, the most common location in males. The lower degree of keratinization in the vulva may influence drug penetration and efficacy. The lower degree of keratinization and the semiocclusive effect of the foreskin have also been proposed as reasons for the higher clearance rates observed among uncircumcised males than circumcised males. 9
In this study imiquimod was significantly more effective than vehicle for the treatment of patients with both large and small warts. The benefit of using a topical therapy rather than an ablative or destructive one, such as cryotherapy, for warts over a large area (up to 5000 mm2 in this study), includes less pain for the patient, increased convenience, and reduction of scarring. The relative benefit of imiquimod treatment versus vehicle appeared to be extremely large for patients with warts larger than 162 mm2, even though the clearance rate among these patients was not substantially different (50%) than for patients with smaller warts. The high relative benefit was substantiated by the fact that warts cleared for none of the patients in the vehicle subgroup.
The duration of patients’ current outbreaks of warts varied from a few weeks to several decades. It is possible that long duration of disease could affect the efficacy of treatment; however, imiquimod provided a statistically significantly greater benefit than vehicle, irrespective of the length of time the patients had had their warts. For patients whose warts were present for longer than 6 months, the relative benefit of imiquimod in comparison with that of the vehicle was large, even though there was a slightly lower clearance rate in this patient population than among those patients whose warts were present for less than 6 months. The large relative benefit of imiquimod for patients who have had their warts for longer than 6 months is likely due to the low clearance rate with vehicle for patients in this subgroup.
The majority of patients in this study had previously received other treatments for genital warts, including physician-administered therapies (cryotherapy, podophyllin, TCA, electrocautery, and laser) and patient-applied podophyllotoxin. Among those patients, the baseline warts that were treated in this study may have been new, recurrent, or recalcitrant warts. Imiquimod was found to be significantly more effective than vehicle in both the subgroup who had previously received treatment and the subgroup who had not. As current ablative and cytodestructive treatments tend not to eliminate HPV in the normal tissue surrounding the wart, recurrences often occur in up to 50% of cases, 6 resulting in many patients returning to the clinic for retreatment. In contrast, for the majority of patients whose warts clear with imiquimod treatment, clearance tends to continue. 1 Stimulation of long-term immunologic memory by imiquimod is proposed to be the key to this long-term successful clearance. 8
It is interesting to note that in this study none of the patients had previously received imiquimod treatment. It has been shown in an open-label study that imiquimod is effective in reclearing external genital or perianal warts that initially clear with imiquimod treatment and then recur. 10 Reapplication of imiquimod 3 times a week for up to 16 weeks, for the small proportion of patients who experienced recurrent warts during 6 months of follow-up, resulted in a total clearance rate of 70% (treatment failure analysis). 10
The Centers for Disease Control and Prevention guidelines for the management of genital warts advocate that the preference of patients should be considered in the decision-making process regarding treatment choice. 11 In a survey of patients participating in a single-group open-label international trial, patients treated with imiquimod 5% cream expressed their satisfaction with this treatment option, as it was convenient, associated with minimal pain, and cleared warts in an acceptable length of time. 12 For the physician, other factors that tend to influence treatment choice include size, duration, and the recurrent nature of warts. This analysis revealed that imiquimod 5% cream was significantly more effective than vehicle cream in all the subgroups examined and that it provides a benefit in many cases that are considered difficult to treat. However, no immunosuppressed or HIV-positive patients were involved in this study.
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