Gotovtseva, Elena P. PhD, MPH*; Kapadia, Asha S. PhD†; Smolensky, Michael H. PhD‡; Lairson, David R. PhD§
GENITAL WARTS IS A highly infectious sexually transmitted disease caused by types 6 or 11 human papillomaviruses (HPV).1 The immune system plays a key role in the control of human HPV infections2; thus, immunodeficient patients, e.g., those infected with the human immunodeficiency virus, have shown poor response to traditional treatment with a high rate of lesion recurrence.3 About 1% of the sexually active US population has clinically visible genital warts4 with the highest prevalence observed among women of 20–24 years of age.5 Benign genital warts cause significant psychosocial problems, including anxiety, embarrassment, anger, and shame,6 and account for substantial health care costs, an estimated $200 million annually in the USA.7
The available treatment options include ablative (e.g., cryotherapy and surgical excision), antiproliferative (podofilox 0.5% solution or gel, and podophyllin 20% solution), cytodestructive [trichloroacetic acid (TCA) 80–90%], and immunomodulatory (imiquimod 5% cream) modalities.8 All treatment options are equally recommended on the basis of preference of the patient, the available resources, and the experience of the health care provider. There is no evidence that any of the available treatments are superior to any other and, in general, all treatments have high rates of treatment failure or recurrence.9
Imiquimod (of the imidazoquinoline drug class) medication demonstrates potent immunomodulating, antiviral, and antiproliferative activities,10,11 with the clinical response to imiquimod accompanied by significant reduction of viral load.12 In clinical trials, imiquimod (Aldara, 3 mol/L Pharmaceuticals, St. Paul, MN) demonstrated 40–77% efficacy in completely clearing baseline warts in immunocompetent patients, although with recurrence rates of between 9 and 23% in different trials.13–15 Imiquimod treatment was proven to be more effective when applied as a 5% rather than a 1% or 2% cream.16 Currently, Aldara 5% cream is used as one of the first-line patient-applied home therapies of genital warts with application at bedtime (an 8–10 hours overnight treatment) three times per week for up to 16 weeks.17 The postmarketing research initiated by 3 mol/L Pharmaceuticals and conducted by the HPV Study Group addressed questions of the efficacy and safety of imiquimod as a function of treatment regimen, i.e., once-daily versus three times per week, in different population groups.14,18,19 As recommendations for the use of imiquimod 5% cream are mostly based on the studies funded by the manufacturer and to perform independent analysis we systemically reviewed the published literature specifically dealing with the role of imiquimod application frequency on therapeutic outcome—wart clearance—and adverse events, using the techniques of meta-analysis. We want to emphasize that our study is not funded by any drug manufacturer.
Clinical trials were identified by searching Medline (1966 to Feb 10, 2007), Scopus (1996 to Feb 10, 2007), and Cochrane Library (Issue 1, 2007) databases using the terms: imiquimod, Aldara, R-837, genital warts, anogenital warts, condyloma acuminata, and the subheading of “randomized clinical trials.”
Types of Studies.
Only randomized controlled trials (RCT) containing data on the three times per week or once-daily dosing regimens of imiquimod 5% cream treatment of external anogenital warts were analyzed.
We used data only from studies on immunocompetent adult patients showing clinically visible and diagnosed warts in the genital, anal, perineal, or perianal area.
Treatment had to be restricted to imiquimod 5% cream applied as monotherapy at bedtime for 16 weeks, either with a frequency of three times per week or once daily.
The beneficial effect (primary efficacy outcome) was assessed by the proportion of patients showing complete clearing of baseline warts by the end of the treatment period. Adverse events were summarized as severe if they required withdrawal of the patient from treatment and moderate/mild if they required the patient be given a rest period from treatment. The harmful effect (primary safety outcomes) was assessed both by the (a) proportion of patients who withdrew from study and (b) proportion of patients who required at least one rest period due to treatment-associated adverse events.
Studies were excluded if they were nonrandomized trials, involved combination therapies, included immunocompromised patients, or consisted of data duplicated from a previous publication.
Data Extraction and Management
Two investigators (EG and AK) extracted and verified the data, including study identification details, patients’ characteristics, study design, and number of patients with efficacy and safety outcomes. The analysis of drug efficacy and safety (study withdrawals) was conducted on the intention-to-treat basis. Data on patients who took at least one rest period from treatment due to adverse events were analyzed on per protocol basis, because patients withdrew from studies for reasons other than treatment-related ones.
Assessment of Quality and Heterogeneity of Included Studies
The quality of the double-blind placebo-controlled studies was assessed using the Jadad three-item, five-point scale.20 A modified Jadad scale was used for open-label studies.21 This scale has a maximum score of 3, limiting assessment to only randomization and dropout/withdrawal components. The clinical homogeneity of studies was assessed based on the study hypothesis, patient inclusion/exclusion criteria, source of the experimental drug used for trial, study design, and outcomes to evaluate drug efficacy and safety. Sex effect, as a source of heterogeneity of effect size, was examined as an aspect of the meta-analysis. Statistical heterogeneity between studies was assessed using the chi squared test for categorical data with 5% level of statistical significance.22
The average effect over all studies was estimated using standard statistical techniques of meta-analysis. Aggregate proportions as summary estimates of effect size were calculated with 95% confidence intervals (CI) as described by Laird and Mosteller.22 The analysis was conducted using a fixed-effects model, if studies were statistically homogeneous, and repeated with a random-effects model. Pooled analysis of complete clearance rate: pw = ∑piwi/∑wi, where pw is the aggregate proportion; pi, the proportion of patients with complete clearance of warts in an individual study; and wi, the weight assigned to individual results. The weights assigned to individual results are in inverse proportion to their variance, thereby giving more weight to larger and less weight to smaller studies.22 Statistical significance of any difference between aggregate proportions for the different application frequencies or between patient subgroups was tested using the z statistic. Statistical analysis was performed with STATA 8.0.
Of the total of 22 identified clinical studies through our literature review, 6 studies met the criteria for inclusion in the analysis (Table 1). All studies were RCT; 4 studies were Phase II open-label trials, using an active comparator and addressing treatment intensity and duration issues, and the other 2 were double-blind placebo-controlled by design. Individual study quality scores are presented in Table 1. All studies were conducted in a similar way, i.e., on adults with clinically diagnosed external anogenital warts, with home-administered treatment using imiquimod 5% cream (Aldara, 3 mol/L Pharmaceuticals) applied at bedtime for a duration of up to 16 weeks, and all used the same outcome measures to assess efficacy and safety. Two studies included both women and men,13,23 2 studies included either circumcised or uncircumcised men,14,18 and 2 studies included only women.19,24
Complete Wart Clearance.
Data were pooled separately for the 3 population subgroups (Table 2). In each subgroup, studies were statistically homogeneous by the chi-squared test (P = 0.907 for circumcised men, and P = 0.196 for women).
Imiquimod Three Times Per Week Versus Once-Daily Regimen
Both in circumcised men (Table 2) and in women (Table 2), there was no difference in aggregate proportions of successfully treated patients between the three times per week and once-daily regimens (z = 0.11, P = 0.9 and z = 0.38, P = 0.7, respectively). Likewise, in a single study with uncircumcised men (Table 2), no difference in the proportion of patients with complete clearance of warts was observed between the two treatment regimens (z = 0.15, P = 0.9). In all cases, similar results were obtained when the data were tested by fixed-effects and random-effects models [Table 2 (see comparison for circumcised men and women)].
Imiquimod: Women Versus Circumcised Men
The pooled effect size was significantly higher in women than in circumcised men, regardless of the drug application frequency (z = 3.9, P = 0.0001 for the three times per week and z = 4.2, P = 0.0001 for the once-daily regimen).
Imiquimod: Uncircumcised Versus Circumcised Men
Imiquimod treatment was more effective in uncircumcised than circumcised men, but only for the three times per week versus once-daily application regimen (z = 3.3, P = 0.001 and z = 1.93, P = 0.054, respectively).
The incidence of withdrawal from studies because of medication-related cutaneous reactions was similar between the 2 compared imiquimod cream application frequency regimens (Table 3). In uncircumcised men, 4 patients (2 in the three times per week group, and 2 patients in the once-daily application group) withdrew from study because of foreskin-associated reactions.
The proportion of female and uncircumcised male patients who required at least one rest period because of local cutaneous reactions was significantly greater with the once-daily than the three times per week application regimen (z = 2.4, P = 0.02 and z = 2.7, P = 0.007, respectively). In circumcised men, such differences were not statistically significant (z = 0.5, P = 0.6) (Table 3).
Imiquimod 5% cream is one of 5 equally recommended treatment regimens against genital warts, and one of 2 equally recommended as self-applied modalities.17 The long duration course of intermittent imiquimod therapy rises the concern that patient compliance may be reduced, thereby compromising the effectiveness of treatment,25,26 and some prescribers may have a notion of more frequent imiquimod treatment schedule. Several individual studies sponsored by the manufacturer were conducted earlier to determine the optimal frequency of imiquimod 5% cream application for the treatment of anogenital warts in different population subgroups, but this is the first independent systematic review and quantitative analysis of the published data on this issue.
All 6 identified studies were RCT, and 4 of them were open label by design. The latter were postmarketing Phase II trials, either using a dose-escalating design for assessment of drug safety and patient tolerance14,18,19 or using an unmasked design for determining the optimal duration of treatment.24 Blinding was unlikely due to the ethical issues for postmarketing research with earlier established imiquimod 5% cream efficacy,13,23 but patients were notified about the uncertainty of the optimal treatment regimen.18 In this case, the modified Jadad scale with maximum score of 3 rather than 5 was commonly used.21,27 In this respect, 5 of the 6 reviewed studies were considered of good quality (a score of ≥2/3 for the open-label studies and a score of 3/5 for the double-blind studies) (Table 1). The low score of 1 out of possible 3 was given to the study of Trofatter et al.,19 a dose-escalating randomized clinical trial, which was published as a brief communication with no report of the number of patient withdrawals and dropouts. Other than this deficiency, the study report contained all the other important information, including patient characteristics, intervention description, drug safety data (e.g., a number of patients requiring rest periods from treatment), and effect size, based on the intention-to-treat analysis; thus, it was included into the meta-analysis. Our inclusive method was tested by weighting the effect sizes by quality scores.28 The effect size was not affected by the low quality score of the Trofatter et al. study,19 where pw (95% CI) = 0.59 (0.50, 0.68) for the 3 pooled studies13,19,24 versus pw (95% CI) = 0.64 (0.53, 0.75) for the 2 pooled studies13,24 (z = 0.2, P = 0.84). Thus, the clinical evidence of drug efficacy and safety appeared to be of reasonable methodological quality.
The identified studies were clinically homogeneous in terms of patient inclusion criteria (immunocompetent adults) and intervention (imiquimod 5% cream applied at bedtime for up to 16 weeks). Because the studies varied by the sex and circumcision status of the participants, a subgroup analysis was conducted to estimate drug efficacy in the comparison of the 2 dosing regimens. This type of analysis was justified by the fact that sex had been identified as a significant factor, and circumcision status and occlusive characteristics of the foreskin had been suggested as important determinants that affect imiquimod 5% cream efficacy and safety.14,15,29 To test the robustness of the quantitative synthesis, both fixed-effects and random-effects statistical models were used.30
The once-daily in comparison with the three times per week application regimen of imiquimod 5% cream did not improve its efficacy in any of the analyzed groups of patients. The revealed differences in the treatment response rate among 3 subgroups of patients could be explained by the type (keratinized vs. partially keratinized and dry vs. moist) of skin on which the warts were located with likely greater drug penetration through the partially keratinized skin and moist environment.
The most frequently reported adverse reactions were local skin and application-site reactions of mild to moderate intensity. In cases of severe reactions, which could lead to withdrawal from study, rest periods of several days were allowed before resumption of treatment.14,15,18,19,23 By the techniques of meta-analysis it was confirmed that both in women and uncircumcised men the proportion of patients who required at least one rest period from treatment was significantly higher with the once-daily than the three times per week application schedule. These findings support current recommendations for scheduling imiquimod 5% cream treatment against genital warts.
One limitation of this study was the indirect comparison of pooled treatment effect estimates (aggregate proportions of completely cured patients), calculated for the once-daily versus three times per week drug application regimens. However, direct comparisons of head-to-head studies14,18,19 took precedence in drawing conclusions based on this systematic review. A second limitation of the study was the use of the modified rather than the validated Jadad scale to assess the quality of the open-label studies. A lack of blinding of outcome assessment may introduce performance bias, which may consequently affect the conclusions of the review. For this reason, we also assessed the quality of the included trials by performing the sensitivity analysis applying both random-effects and fixed-effects statistical models. It was shown that effect size was similar in double-blind and open-label clinical trials (Table 2). In spite of the study limitations, the collected evidence is nonetheless sufficiently strong enough to recommend imiquimod 5% cream as a three times per week regimen in all population subgroups, and this supports current recommendations. The data of the published studies also indicate patient skin type should be taken into account in developing treatment algorithms. Recent studies suggest the duration of treatment course may be reduced, as imiquimod plays a role in triggering cell-mediated immune responses24; future research on this issue is required before changes in treatment are instituted.
The optimal frequency of imiquimod 5% cream treatment for external anogenital warts in adult immunocompetent women as well as circumcised and uncircumcised men is three times per week. Imiquimod 5% cream is an effective and safe nonsurgical home-applied treatment modality when the three times per week regimen is utilized.
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