Topically Applied Treatments for External Genital Warts in Nonimmunocompromised Patients

A Systematic Review and Network Meta-analysis

J.M. Jung; C.J. Jung; W.J. Lee; C.H. Won; M.W. Lee; J.H. Choi; S.E. Chang


The British Journal of Dermatology. 2020;183(1):24-36. 

In This Article


Although several systematic reviews on topical agents for genital warts have been performed,[57–59] they were conducted using conventional meta-analysis. In contrast, we have used NMA to evaluate the evidence for topical agents' efficacy for treating genital warts. Unlike traditional meta-analysis, where two interventions are compared using pooled head-to-head data, NMA allows not only for comparisons between more than two interventions, but also for comparisons between interventions that have not been contrasted directly in RCTs.[13] These advantages enable clinicians to make informed treatment decisions that are based on evidence from NMA, particularly in the absence of clinical trials directly comparing candidate treatments. In this study, we systematically reviewed all topically applied treatment options for external genital warts that were studied in at least one RCT and met our eligibility criteria.

All topical agents included in this study were statistically superior to placebo in terms of complete clearance of lesions, which is consistent with results from previous conventional meta-analyses.[57–59] In their meta-analysis, Yan et al. reported that both imiquimod 5% and podophyllotoxin 0·5% were significantly better than the placebo for complete lesion clearance.[59] However, they were unable to conclude superiority, inferiority or equivalence of imiquimod and podophyllotoxin due to the absence of a direct comparison. A subsequent RCT demonstrated the equivalence of imiquimod 5% cream and podophyllotoxin 0·5% solution.[33] In the present study, although the NMA included all direct and indirect comparisons, we found that podophyllotoxin 0·5% solution was significantly better than imiquimod 5% cream in terms of complete clearance. In this study, we also included nonconventional or newly emerging modalities reported in at least one RCT. Among these agents, idoxuridine, polyhexamethylene biguanide, cidofovir and SB206 12% were found to be promising in lesion clearance. However, the limited number of clinical trials on these agents and the high or unclear overall risk of bias in those studies[29,30,36,42,52] restricted the strength of these observations.

We found only two studies, by the same author, in which topically applied interferon alpha with used for external genital warts. These studies found high efficacy, which could be attributed to a regimen of three-times-daily application.[46,48] The reproducibility of these results could not be confirmed, because interferon alpha is poorly absorbed in normal skin, limiting the results to warts located on the mucosal epithelium.[60]

The therapeutic efficacy of sinecatechins was significantly lower than that of other conventional, self-applied topical treatments, such as imiquimod 5% or podophyllotoxin. Considering that the placebos in studies on sinecatechins[27,43,50] were more efficacious than those in other studies, our results should be confirmed via clinical trials in the future.

The current study revealed the similarity in recurrence among all treatment modalities in entire comparisons. Modalities such as sinecatechins or imiquimod, which require longer treatment periods to remove warts, tend to be better options regarding recurrence according to the P-score analysis. This could be attributed to their mechanism of action, which includes provoking a host immune response.[20,27]

Imiquimod, an immune response modifier,[21] and sodium nitrite with citric acid, a nitric oxide-releasing agent that can also activate immune response in the skin,[38] offered the best options in terms of safety. On the other hand, cytodestructive agents, such as podophyllin or podophyllotoxin,[9] were related to significantly higher overall rates of adverse events compared with imiquimod.

Creams with lower than 5% concentration of imiquimod have been examined in several RCTs.[17,21,24,39,45,47] The authors surmised that creams with lower imiquimod concentrations would reduce the treatment period by increasing the application frequency, as well as reducing the incidence of treatment-related adverse events. However, in our analysis, imiquimod 2·5% or 3·75% showed significantly lower efficacy than imiquimod 5% in clearing genital warts, while the overall rates of treatment-related adverse events were not significantly different. Only imiquimod 1% was associated with a significantly lower incidence of adverse events than imiquimod 5%, but it showed lower efficacy in lesion clearance. While imiquimod 2% was significantly better at lesion clearance than imiquimod 5%, the patients applied the cream twice daily in one of the two studies on imiquimod 2%.[45] As a result, the P-score analysis showed inferiority over imiquimod 5% in terms of safety.

SAEs or patients who withdrew because of treatment-related adverse events were quantitatively and qualitatively analysed in this study. Because the two variables used in this analysis were the number of patients with SAEs or patients who withdrew because of treatment-related adverse events, and the size of the safety population, our results were influenced by both the treatment period and each agent's safety characteristics. With longer treatment durations, the likelihood of a patient experiencing an SAE or withdrawal from the trial increased. There was a tendency for topical agents with relatively longer treatment periods to be ranked at the bottom of our analysis. All specific treatment-related SAEs were limited to local reactions, and death or permanent damage related to treatment was not reported in any RCTs included in this study.

The P-score measures the mean certainty that a treatment is better than another treatment, based only on the point estimates and standard errors of the frequentist NMA estimates.[61] Therefore, P-scores of unconventional therapies should be interpreted with caution because of the large uncertainties with effect estimates. There can also be large uncertainties in the P-score analyses from NMAs regarding recurrence and patients with SAEs or who withdrew because of treatment-related adverse events, considering the large uncertainties with effect estimates in general in those NMAs. Clinicians should be aware that P-scores have no major advantage compared with CIs when choosing one treatment over another.[15]

This study is not without limitations. Firstly, the heterogeneity of each study's baseline characteristics, such as male-to-female ratio, and wart number, size, site and duration, were not considered in the analysis. Secondly, the results can be influenced by variation in choice of study design, although global consistency was supported by statistical tests for all outcomes. Thirdly, the number of RCTs included was relatively small considering the number of treatment modalities, such that some comparisons in the NMA relied on only one study. In addition, only eight treatment modalities could be evaluated in terms of all four outcomes: complete clearance, recurrence, adverse events and patients with SAEs or patients who withdrew because of treatment-related adverse events. Lastly, one or more domains of the risk-of-bias assessment in all of the included studies were unclear or high, which decreased this study's overall evidence level.

In conclusion, all topically applied treatment options included in this analysis were efficacious and well tolerated, although they each had advantages and disadvantages affecting the four outcomes assessed. Cytodestructive agents, such as podophyllin and podophyllotoxin, were highly efficacious in rapidly clearing lesions, but they were more likely to have safety concerns. In clearing genital warts, sinecatechins were significantly less efficacious than podophyllotoxin 0·5% or imiquimod 5%. Immune-modifying or immune-enhancing agents, such as imiquimod and sinecatechins, took longer to achieve resolution, and therefore compliance with treatment was another factor to be considered when choosing these therapeutic agents. Unconventional therapies were found to be at least comparable with conventional therapies for eradicating external genital warts.