Adverse Effects of Treatments for Anogenital Warts in Non-immunocompromised Adults: A Network Meta-analysis of Randomized Controlled Trials

Abstract

Introduction

International guidelines for the management of anogenital warts (AGWs) propose multiple first-line options but do not prioritize treatments based on safety or tolerability. This study aimed to compare the safety profiles of topical, systemic, and ablative treatments used for external AGWs in immunocompetent adults.

Methods

A systematic review and frequentist network meta-analysis of randomized controlled trials published through August 2025 was performed. Adverse events (AEs) were classified as low-, moderate-, or high-grade local AEs (LGL, MGL, HGL) and low-grade general AEs (LGG). Relative risks were estimated using random-effects models with placebo as the reference.

Results

We included 107 RCTs involving 12,423 participants. Ablative procedures were associated with higher rates of moderate-to-severe local AEs compared with topical therapies. Among topical treatments, imiquimod 5% and cidofovir cream were associated with lower rates of severe AEs, whereas podophyllotoxin was more often associated with LGL. SUCRA rankings placed topical treatments above ablative therapies in terms of tolerability. Cidofovir cream demonstrated the best safety profile, followed by imiquimod 5%.

Conclusion

This network meta-analysis highlights significant differences in tolerability across AGW treatments and offers a comparative framework for patient-centered therapeutic decision-making. It also emphasizes the need for standardized AE reporting in future trials.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1007/s13555-026-01857-0.

Key Summary Points

Why carry out this study?

Multiple first-line treatments are available for anogenital warts, but their tolerability profiles remain poorly compared

Treatment choice in clinical practice is often guided by experience rather than robust comparative safety data

This study compared the adverse event profiles of topical, systemic, and ablative treatments for anogenital warts using a network meta-analysis

What was learned from the study?

Topical treatments showed overall better tolerability than ablative approaches, which were associated with higher rates of moderate-to-severe adverse events

Imiquimod 5% and cidofovir cream appear to offer favorable safety profiles and may be preferred when tolerability is a priority

Standardized reporting of adverse events is needed to improve future treatment comparisons

Introduction

Anogenital warts (AGWs), or condylomata acuminata, are a common manifestation of human papillomavirus (HPV) infection, usually caused by low-risk genotypes 6 and 11. Although benign, AGWs substantially affect patients’ psychosocial and sexual well-being because of stigma, recurrence, and treatment burden. They also represent a considerable economic burden, with estimated costs per case ranging from 124 to 893 USD [1].

A wide range of therapeutic options exists, including topical agents, such as 5-fluorouracil (5-FU), imiquimod, and podophyllotoxin, and ablative methods, such as cryotherapy, electrosurgery, conventional surgery, and CO₂ laser. These treatments are generally considered to have comparable efficacy, and in everyday practice, the choice often depends on clinician experience, tolerability, patient preference, and cost rather than on robust comparative safety data.

Current guidelines, including those from the Centers for Disease Control and Prevention (CDC) [2] and the European/International Union against Sexually Transmitted Infections (IUSTI) [3], recommend several first-line options for external AGWs. These include patient-applied treatments (imiquimod 3.75% or 5%, podophyllotoxin 0.5%, sinecatechins 15%) and provider-administered therapies (cryotherapy, surgical excision, electrosurgery, trichloroacetic acid), but they do not define a clear therapeutic hierarchy based on safety or tolerability.

Previous network meta-analyses (NMAs) by Barton et al. [4] and Bertolotti et al. [5] primarily focused on efficacy and did not comprehensively assess treatment-related adverse events (AEs). Jung et al. [6] evaluated both efficacy and safety but restricted the comparison to topical therapies, limiting the ability to position topical compared with ablative or systemic treatments in terms of tolerability.

The safety profiles of AGW treatments differ considerably. Cryotherapy can cause pain, blistering, and pigmentary changes. Surgery is associated with postoperative pain, whereas electrosurgery and CO₂ laser may induce significant per-procedural pain. Trichloroacetic acid (TCA) frequently causes burning and local ulceration.

The primary objective of this study was to compare the AEs associated with the most commonly used local and systemic treatments for external AGWs in immunocompetent adults. By integrating safety outcomes from RCTs in an NMA framework and interpreting them alongside existing efficacy data, we aimed to identify treatments that offer the most favorable balance between tolerability and therapeutic benefit and to inform their positioning as first-line options.

Methods

Study Design and Data Sources

This NMA is based on a systematic review (SR) that was used to inform the 2024 recommendations of the French Haute Autorité de Santé (HAS) [7]. The protocol was registered in PROSPERO (CRD42023399791; Appendix 1–2). The SR followed the PRISMA Statement [8], and the present NMA adheres to the PRISMA extension for NMA, using the same initial database as the published SR.

A systematic search of two electronic databases was conducted from inception to August 2025. Details of the search strategy, selection process, and data extraction are provided in Appendix 1–2.

Eligibility Criteria

We included randomized controlled trials (RCTs) that met the following criteria: (1) population: immunocompetent adults and pregnant women with a clinical diagnosis of external AGWs; (2) intervention: topical, oral, intralesional, systemic, or ablative treatments; (3) comparator: placebo or an active comparator; (4) design: parallel-group RCTs.

We excluded studies in patients who were immunosuppressed, individuals living with HIV, and pediatric populations. The present article is based exclusively on previously published studies and does not involve any new research on human or animal subjects by the authors.

Network Meta-analysis

We performed an NMA that combined all available direct and indirect comparisons of AGW treatments. This approach allows comparison of treatments that have not been directly compared within the same RCT by using a common comparator [9]. Placebo served as the reference treatment for indirect comparisons, although it is rarely used in routine clinical practice.

For RCTs assessing doses lower or higher than those recommended in current guidelines, all reported dosages were included in the network. A frequentist framework with random-effects models was used, assuming a common between-study heterogeneity variance across all comparisons. Only the main connected network was retained for the NMA, and isolated sub-networks were excluded to preserve analytical consistency. Network geometry was assessed through graphical examination of connections among interventions, with each node representing an intervention and node size proportional to the number of allocated patients. The thickness of connecting lines was inversely proportional to the variance between two interventions [10].

Outcomes and Definitions

The patient was the unit of analysis. AEs were analyzed using a per-protocol (PP) approach. AEs were categorized as low-grade local (LGL) AEs with mild local effects such as stinging, irritation, and erythema, medium-grade local (MGL) AEs with moderate local reactions such as skin burns, soiling, minor bleeding, erosion, and infection, high-grade local (HGL) AEs with severe local reactions such as blisters or ulcerations, and low-grade general (LGG) AEs with low-intensity systemic effects, such as pain requiring simple analgesics.

Statistical Analysis

We used the netmeta R package (version 8.0; https://CRAN.R project.org/package = netmeta) [11] to perform pairwise and network comparisons of each active treatment versus placebo. Four forest plots were generated for LGL, MGL, HGL, and LGG using random-effects models, with relative risks (RRs) and 95% confidence intervals (CIs).

To explore inconsistency within the networks, we generated net heat plots, which visually display areas of potential inconsistency through color shading [12].

We ranked treatments using the Surface Under the Cumulative Ranking curve (SUCRA). SUCRA values range from 0 to 1 and represent the probability that a given treatment is at a particular rank regarding AE risk, with values closer to 1 indicating a higher probability of being among the worst (i.e., higher AE risk).

Risk of Bias Assessment

The risk of bias (ROB) of the included RCTs was assessed using the Cochrane Collaboration ROB tool [13]. Details of the ROB assessment are provided in Appendix 6. The SR was evaluated using the PRISMA 2020 checklist (Appendix 7).

Results

Characteristics of Included Trials

Of 287 records identified in the initial search, 203 studies met the SR inclusion criteria, and 107 RCTs including 12,423 patients were eligible for the NMA after applying the exclusion criteria.

For LGL, 47 RCTs (5244 patients) were included; for MGL, 52 RCTs (7125 patients); for HGL, 32 RCTs (5324 patients); and for LGG, 41 RCTs (5529 patients). Further details of the included and excluded studies are provided in Appendices 3–5.

Risk of Bias

Of the 107 RCTs assessed with the Cochrane ROB tool, 85 were judged at high risk of bias, 16 at intermediate risk, and 6 at low risk (Appendix 6). The SR was assessed using the PRISMA 2020 checklist and judged to comply with its main requirements (Appendix 7).

Adverse Events

The network included multiple topical, systemic, and ablative interventions, which were directly or indirectly connected via shared comparators. Placebo, imiquimod 5%, and podophyllin were the most frequently evaluated treatments (Fig. 1).

Fig. 1.

Complex network generated from the included studies. A Low grade local, B medium grade local, C high grade local, D low grade general. The compared treatments are connected directly or indirectly through one or more "comparators." The thicker the line, the higher the number of studies including these comparisons

Low-Grade Local AEs (LGL)

Topical treatments imiquimod 5% (RR 2.09; 95% CI 1.32–3.31) and 5-FU 5% (RR 5.47; 95% CI 2.23–13.38) were associated with increased LGL compared with placebo. Among first-line options, cryotherapy (RR 3.77; 95% CI 1.60–8.87) emerged as one of the treatments most likely to induce LGL. Podophyllotoxin 0.5% formulations showed a broadly similar tolerance profile, with a significant signal for the solution (RR 2.54; 95% CI 1.41–4.59). Intralesional treatments, including intralesional 5-FU (RR 6.20; 95% CI 2.06–18.62), were also associated with LGL.

Medium-Grade Local AEs (MGL)

For MGL, 5-FU 5% (RR 7.51; 95% CI 1.09–51.85), imiquimod 5% (RR 2.83; 95% CI 1.21–6.67), and KOH (RR 9.18; 95% CI 1.18–71.67) were associated with increased risk. Podophyllotoxin 0.5% gel (RR 18.97; 95% CI 3.58–100.46) showed a particularly high risk compared with other topical formulations. Among ablative treatments, CO₂ laser presented the highest MGL risk (RR 33.60; 95% CI 3.96–285.21). Cryotherapy combined with an oral retinoid (RR 9.84; 95% CI 1.21–80.26) had a higher MGL risk than cryotherapy alone (RR 6.26; 95% CI 1.37–28.68).

High-Grade Local (HGL) AEs

Electrocoagulation (RR 32.96; 95% CI 2.04–533.24) and podophyllotoxin 0.5% solution (RR 5.75; 95% CI 1.18–28.07) were significantly associated with HGL. No statistically significant associations with HGL were observed for 5-FU 5%, imiquimod 5%, CO₂ laser, or cryotherapy in this analysis.

Low-Grade General (LGG) AEs

Surgical excision was associated with an increased risk of LGG (RR 11.47; 95% CI 2.21–59.53). No significant associations were found for 5-FU 5%, CO₂ laser, intralesional bleomycin, or interferon-β injections, suggesting that these treatments do not substantially affect LGG outcomes (Fig. 2).

Fig. 2.

Forest plot of the relative risk (RR) estimates between each treatment and the reference placebo for patients with adverse events. A Local low grade, B local medium grade, C local high grade, D general low grade. Data presented as RR (95% CI). 5-FU 5 fluoro-uracil, 5-FU intralesional 5 fluorouracil, ablative treatment (surgery or electrosurgery or CO₂ laser or cryotherapy), Cryo cryotherapy, Electro electrosurgery, IFN B interferon B, Imi imiquimod, INF cream interferon cream, Mycobac IL mycobacterium intra intralesional, PDT photodynamic therapy, Podo podophyllin 20–25%, Podotox cr podophyllotoxin cream, Podotox sol podophyllotoxin solution, podotox gel podophyllotoxin 0.5% gel, Podotox sol + cr podophyllotoxin 0.5% solution + cream, Polyph polyphenon, KOH potassium hydroxide, TCA trichloroacetic acid, Vit c vitamin c, Cryo + Podo cryotherapy + podophyllin, Cryo + Podotox cryotherapy + podophyllotoxin, INF alfa 2-b interferon alfa 2-b

Network Inconsistency and SUCRA Rankings

Net heat plots (Fig. 3) showed notable inconsistencies in the LGL network, particularly in comparisons between placebo and podophyllotoxin 0.5% solution. In the MGL network, marked inconsistency was observed in trials evaluating the combination of imiquimod 5% and podophyllin. In the LGG network, inconsistencies were noted between 5-FU 5% and podophyllin and between placebo and 5-FU 5%. The HGL network appeared globally consistent.

Fig. 3.

Net heat plot. Assessment of consistency between direct and indirect evidence. A Local low grade, B local medium grade, C local high grade, D general low grade. Horizontal: detached comparisons; vertical: comparisons observed in the network; warm color in the net heat plot indicates that significant inconsistency may arise from a specific comparison, and this trend is illustrated by the intensity of the color; gray: contribution of each direct comparison with the network estimates

Based on SUCRA, 5-FU 5% had the highest probability of being among the worst treatments for LGL (SUCRA 0.81) and also ranked high for MGL (0.60), similar to cryotherapy (LGL 0.73; MGL 0.58). Imiquimod 5% showed a more favorable profile (LGL 0.52; MGL 0.36). KOH and TCA carried non-negligible MGL risks (SUCRA 0.64 and 0.69, respectively). Podophyllotoxin 0.5% gel had the highest MGL risk among topical treatments (SUCRA 0.79).

Among physical treatments, CO₂ laser was the riskiest for MGL (SUCRA 0.87), while electrocautery was the riskiest for HGL (0.86). Surgery also showed substantial risk (SUCRA 0.55 for MGL; 0.77 for LGG). In contrast, cidofovir cream displayed consistently low SUCRA values (LGL 0.26; MGL 0.12; HGL 0.12), indicating the most favorable overall safety profile (Fig. 4).

Fig. 4.

Surface under the cumulative ranking curve (SUCRA) analysis representing the risk of adverse effect across treatment modalities for anogenital warts. LGL low grade local, MGL medium grade local, HGL high grade local, LGG low grade general. Green < 0.25; yellow (0.25 < 0.5); orange (0.5 < 0.75); red > 0.75

Discussion

This NMA is, to our knowledge, the first to primarily address the comparative safety of treatments for external AGWs, an aspect that remains underrepresented in a literature largely focused on efficacy. The robustness of our findings is supported by the large number of included RCTs and patients. In addition, the use of a structured systematic review and standardized tools such as the Cochrane ROB instrument strengthens the methodological reliability of the analysis.

Our results suggest that, in general, topical treatments are better tolerated than ablative approaches, consistent with previous comparative trials evaluating TCA versus cryotherapy or imiquimod 5% versus cryotherapy [14, 15]. This supports the concept of a less invasive, topical-first strategy when clinically appropriate. However, adherence to topical treatments is often suboptimal. The World Health Organization and dermatology-specific studies estimate that one-third to one-half of patients do not adequately adhere to topical regimens [16, 17].

Imiquimod 5% was associated with a significant risk of LGL, while risks for MGL and HGL remained moderate. This requires nuanced interpretation. Yentzer et al. [18] have suggested that mild, expected local reactions may paradoxically support adherence by reinforcing the perception of an active and effective treatment, as shown in actinic keratoses. Furthermore, LGL may reflect local immune activation and a stronger inflammatory response, which has been linked to greater therapeutic benefit in some settings [19]. Thus, for imiquimod, frequent LGL might represent a manageable and expected trade-off rather than a strict disadvantage, provided that patients are adequately counseled.

Our findings are in line with the NMA by Jung et al. [6] and the meta-analysis by Yan et al. [20], confirming that podophyllotoxin is associated with higher AE rates than imiquimod. Imiquimod 5% does not appear to carry a higher AE risk than imiquimod 3.75%, contrary to the conclusions of O’Mahony et al. [21], who favored 3.75% based on its lower concentration and simplified regimen. For polyphenon E (sinecatechins), no major difference in AE risk between 10% and 15% concentrations has been demonstrated, supporting the hypothesis that the active compound rather than its dose predominantly drives tolerability [22].

CO₂ laser showed the highest risk of medium-grade local adverse events. These events mainly consisted of transient post-procedural pain, minor bleeding, erosions, and local inflammatory reactions, which are expected consequences of tissue ablation and are generally self-limited. Importantly, no significant increase in high-grade local adverse events was observed, suggesting that although the CO₂ laser is associated with substantial local morbidity, severe complications remain uncommon.

Cidofovir cream emerged in our analysis as the treatment with the most favorable safety profile, consistent with previous work that did not report major AEs [6]. Nonetheless, its role in treatment algorithms remains unclear. Although cidofovir appeared among the treatments with the most favorable safety profile, its efficacy remains uncertain and should be balanced against the efficacy reported for more established ablative therapies such as surgery, electrosurgery, and photodynamic therapy. Cidofovir is also absent from IUSTI’s main treatment flowcharts [3]. This suggests that cidofovir may be preferentially considered in selected clinical settings where tolerability outweighs the need for maximal efficacy.

Our NMA also highlights the considerable heterogeneity in how AEs are defined and graded across AGW trials. Some studies, such as that by Tatti et al. [23], classify local reactions (e.g. edema, erosion, ulceration) into mild, moderate, and severe categories without using a standardized grading scale, making inter-study comparisons difficult. Subjective symptoms like pain are influenced by individual thresholds and psychological context, and many studies did not use validated tools such as the visual analog scales [24]. The assessment of visible signs such as erythema often relies on clinical judgment, which may vary with the observer’s experience and examination conditions. More objective methods, including computer-assisted image analysis [25], could help standardize the evaluation of erythema and better distinguish physiological from pathological changes.

Several limitations should be acknowledged. First, we did not adjust for baseline heterogeneity in important factors such as the sex ratio, number, size, and location of lesions, which may influence tolerability. Second, although global consistency was acceptable across most networks, some comparisons were based on relatively small sample sizes, and net heat plots revealed local inconsistencies, especially for certain topical combinations and placebo contrasts. Third, many included RCTs were judged to have high or unclear risk of bias, which may affect the certainty of the evidence. Finally, only the main connected component of the network was analyzed, leading to the exclusion of some potentially relevant treatments (e.g., oral isotretinoin) to maintain coherence.

Despite these limitations, the present study provides clinically relevant comparative information on the tolerability of commonly used AGW treatments, which has been lacking in prior work largely focused on efficacy alone.

Conclusion

This NMA highlights substantial differences in the adverse event burden of treatments for AGW. Overall, topical therapies demonstrated more favorable tolerability profiles than ablative approaches, which were more frequently associated with moderate-to-severe local or systemic adverse events. Among topical treatments, imiquimod 5% and cidofovir cream consistently showed lower probabilities of moderate and severe adverse events.

By providing a comparative ranking based solely on tolerability outcomes, these findings offer a safety-oriented framework to support individualized treatment discussions for immunocompetent adults with external AGWs. Finally, this work underscores the need for standardized definitions and grading of adverse events in future randomized controlled trials to improve the comparability and clinical interpretation of safety data.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Antoine Bertolotti, Elisa Joly, and Reda Saib. conceptualized and designed the study. Antoine Bertolotti, Elisa Joly, and Reda Saib participated in data acquisition and interpretation. Babacar Tounkara and Cyril Ferdynus. were responsible for the statistical analysis and contributed to data interpretation. Reda Saib, Elisa Joly, and Antoine Bertolotti drafted the initial manuscript. Sebastien Fouéré and Christian Derancourt critically reviewed the manuscript. All authors read and approved the final manuscript.

Funding

No funding or sponsorship was received for this study. The Rapid Service Fee was funded by The Research Direction of The University Hospital of La Reunion.

Data Availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Conflict of Interest

Réda Saib, Elisa Joly, Sébastien Fouéré, Christian Derancourt, Babacar Tounkara, Cyril Ferdynus, and Antoine Bertolotti have no conflicts of interest to disclose.

Ethical Approval

This article is based on previously conducted studies and does not involve any new studies with human or animal subjects performed by any of the authors.