This quantitative systematic review demonstrates that imiquimod is effective in the self-treatment of genital warts at home, at the cost of some adverse effects associated with enhanced inflammatory reactions that were reversible when treatment was stopped temporarily. Studies were clinically homogeneous in terms of patient inclusion criteria and those who were excluded. For instance, the five studies used for data pooling all excluded patients with HIV infection. They were also homogeneous in terms of the treatment periods (8-16 weeks). Most used thrice-weekly applications though one [26
] used daily application for five days with a two-day rest. In the latter case the maximum number of applications was 60, as compared to 48 in most others. The exception was a study that used a 24-hour application three times a week [22
], but in that case the duration was only eight weeks. Maximum exposure to imiquimod was therefore similar.
A possible source of heterogeneity was the source of the imiquimod used in the trials. For five trials this was the formulation produced by 3M Pharmaceuticals, at 1% or 5% strength. One trial used a different strength (2%) [26
], and unclear formulation. Sensitivity analysis therefore examined the highest concentration of imiquimod in all trials, that is data on 2% or 5% creams (Figure ), and with 5% and 1% imiquimod creams separately.
Outcomes used to demonstrate efficacy were also homogeneous. These were patients with warts completely cleared, or with wart area reduced by half. Wart measurement was uniformly objective, with mapping and even with photographs to ensure objectivity. One outcome not reported, but one that could be inferred, was that of patients with warts completely cleared by the end of treatment, and with no recurrence of warts during the 10-16 weeks of follow up.
Numbers needed to treat for these outcomes were 2 (complete clearance or at least 50% reduction in wart area) or 3 (warts completely cleared by the end of treatment, and with no recurrence). This occurred despite very different absolute percentages of patients achieving the outcome, because placebo rates were high (20%) with the easiest outcome (at least 50% reduction in wart area) and as low as 4% with the hardest (warts completely cleared by the end of treatment, and with no recurrence). This is shown in Figure . Complete wart clearance by the end of treatment was 40-50% with 5% imiquimod (Figure , Table ), with application three times a week. This is slightly less than the 62% clearance rate seen in a small non-randomised open study comparing this application strategy with daily application [27
] published after searching had been completed.
Percentage of patients with different outcomes with placebo (pink) and imiquimod (blue)
There was a clear concentration-response, with 5% imiquimod consistently achieving higher clearance rates and lower NNTs than 1% (Table ). Results for women were consistently better than for men for complete clearance, though not for at least 50% reduction in wart area (Table ).
Recurrence of warts was described for patients in whom warts had cleared. The results of the pooled analysis tell us that about 50% of patients will have their warts cleared with 5% imiquimod, and that 40% will have warts cleared and there will be no recurrence. The implication is that for 4 out of 5 patients in whom warts clearance is achieved, no recurrence will occur. For the three large trials [21
] 121/254 patients had warts cleared at the end of treatment with 5% imiquimod, and only 27/121 (22%) of these has a recurrence. It is unclear whether this recurrence rate of 22% can be compared with the higher recurrence rates (up to 95% with laser therapy) quoted for other treatments [7
Adverse events were well recorded, especially withdrawal due to lack of effect and adverse events [13
], and the methods used to collect adverse event information given in the five large trials (supplementary file 4). Adverse events were actively sought at clinic visits in most studies, and diaries and prompts can lead to increased reporting of adverse events [28
]. Local events related to enhancement of the inflammatory response, erythema, itching, burning, irritation and tenderness were common (supplementary file 4), even at a moderate or severe intensity. Adverse events caused few patients to withdraw (about 2%), and this was not significantly different from placebo. Fewer patients given imiquimod withdrew because of lack of efficacy (Table ).
The quality of the evidence was good on several counts. Not only was there clinical homogeneity, but the quality scores were 3 or 4, and scores of 3 or more have been shown [29
] to be associated with less likelihood of bias. Moreover for most of the efficacy outcomes there was enough data and a large enough effect to make it likely that the results would be free of any chance effects [31
]. Efficacy was robust to sensitivity analysis, and there was a dose-response.
What the review cannot tell us is whether there are different patient groups (other than men and women) who might differentially benefit. For instance, there was no opportunity to perform an analysis based on the severity of the warts by number or area. That analysis could only be done using detailed information on individual patients. Nor was it possible to derive any information on the many practical issues that surround management of genital warts, such as personal hygiene, the ability to see the warts to adequately apply the treatments, unprotected sexual intercourse, clothing or other infections. Many of these practical problems may be beyond the scope of randomised trials, and therefore reviews of them.
The results of this systematic review complement guidelines for the diagnosis and treatment of genital warts in primary care [3
]. They demonstrate imiquimod to be effective in home application, though not in patients with HIV infection with the evidence presently available [24
]. Rates of first attacks of genital warts have been rising for a decade [32
], and an average primary care group of 100,000 population will have about 240 such cases a year, with as many again of recurrences and reregistered cases [32
]. Pressures on hospital-led clinics, or their inaccessibility in rural areas, together with the availability of treatments like imiquimod that can be used at home, makes recognition of its role in primary care sensible [4
Practitioners often want information about the relative efficacy and harm of different treatments for the same complaint, and, increasingly, about relative cost-effectiveness. We could not find any systematic review of other treatments for genital warts in this setting, particularly for podophyllotoxin.