Local management of anogenital warts in immunocompetent adults: Systematic review and pooled analysis of randomized-controlled trial data

Published:April 09, 2019DOI:https://doi.org/10.1016/j.jaad.2019.04.008
      To the Editor: Although several treatments exist for anogenital warts, no clear treatment hierarchy is mentioned in the latest guidelines.
      • Gilson R.
      • Nugent D.
      • Werner R.N.
      • et al.
      2018 European guideline for the management of anogenital warts.
      Centers for Disease Control and Prevention
      Anogenital warts-2015 STD treatment guidelines.
      We conducted a pooled analysis of randomized-controlled trials (RCTs) of anogenital wart treatments (provider-administered therapies and patient-administered treatments reported in at least 1 parallel treatment group). Our analysis covered a large number of patients and supplements meta-analyses performed with studies that included only 2 treatment groups.
      Our systematic review included RCTs of anogenital wart treatments published up to August 1, 2018, following the methodology described in our systematic review protocol (Prospero no. CRD42015025827).
      • Bertolotti A.
      • Dupin N.
      • Bouscarat F.
      • et al.
      Cryotherapy to treat anogenital warts in nonimmunocompromised adults: systematic review and meta-analysis.
      In total, 70 RCTs involving 9931 individual patients were included. A high risk of bias was identified in 66 RCTs.
      • Bertolotti A.
      • Milpied B.
      • Fouéré S.
      • et al.
      Methodologic gaps and risk of bias in randomized controlled trials of local anogenital wart treatments.
      Our main pooled analysis results are summarized in the Table I.
      • Gilson R.
      • Nugent D.
      • Werner R.N.
      • et al.
      2018 European guideline for the management of anogenital warts.
      • Stone K.M.
      • Becker T.M.
      • Hadgu A.
      • et al.
      Treatment of external genital warts: a randomised clinical trial comparing podophyllin, cryotherapy, and electrodesiccation.
      The complete clearance rate was higher for provider-administered therapies (92%) than patient-administered treatments (56%), but the recurrence rate was lower for patient-administered treatments (6%) than provider-administered therapies (29%). Surgery was painful in 48% of cases, and CO2 laser was associated with a recurrence rate of 31%. For electrosurgery, the recurrence rate was high, side effects were low, and the clearance rate was low due to the high number of patients lost to follow-up in the study by Stone et al;
      • Stone K.M.
      • Becker T.M.
      • Hadgu A.
      • et al.
      Treatment of external genital warts: a randomised clinical trial comparing podophyllin, cryotherapy, and electrodesiccation.
      it would have been 79% with a per-protocol analysis. Trichloroacetic acid was associated with a high clearance rate, a low recurrence rate, and few side effects compared with cryotherapy.
      • Bertolotti A.
      • Dupin N.
      • Bouscarat F.
      • et al.
      Cryotherapy to treat anogenital warts in nonimmunocompromised adults: systematic review and meta-analysis.
      The latest guidelines
      • Gilson R.
      • Nugent D.
      • Werner R.N.
      • et al.
      2018 European guideline for the management of anogenital warts.
      include 5-fluorouracil cream but fail to mention potassium hydroxide. Our analysis yielded a high clearance rate and a low recurrence rate for both treatments, suggesting that potassium hydroxide could also be included as first-line treatment in future guidelines; besides, 5-fluorouracil cream caused more low- and medium-grade local side effects than potassium hydroxide. Podophyllotoxin 0.5% solution or cream seemed as effective as cryotherapy or imiquimod but caused more general side effects. Cryotherapy, CO2 laser, and podophyllotoxin 0.5% solution or cream caused less high-grade local side effects than other treatments. High-grade local side effects were rarely reported for provider-administered therapies with local anesthesia. They seemed equivalent in number between patient-administered treatments and provider-administered therapies but involved different consequences. Recurrent pain or burns after application of patient-administered treatments (eg, imiquimod) can lead to nonadherence, unlike after provider-administered therapies requiring only a single application (eg, CO2 laser).
      Table IPooled-analysis of potential first-line local AGW treatments
      First-line treatments mentioned in current international recommendations.
      • Gilson R.
      • Nugent D.
      • Werner R.N.
      • et al.
      2018 European guideline for the management of anogenital warts.
      Potassium hydroxide is not included in those guidelines, but our pooled-analysis results indicate that it could be.
      for all judgment criteria
      TreatmentNo. RCTs (total no. ITT patient population)Clearance% with type of side effect/outcome quartile
      Outcomes are graded best (Q1) to worst (Q4) by quartile.
      RecurrenceLGLMGLHGLLGG
      Patient-administered
       5-Fluorouracil cream6 (393)68/Q213/Q284/Q468/Q48/Q216/Q2
       Potassium hydroxide
      First-line treatments mentioned in current international recommendations.
      • Gilson R.
      • Nugent D.
      • Werner R.N.
      • et al.
      2018 European guideline for the management of anogenital warts.
      Potassium hydroxide is not included in those guidelines, but our pooled-analysis results indicate that it could be.
      2 (54)63/Q26/Q117/Q150/Q3NR17/Q2
       Podophyllotoxin 0.5% solution13 (829)59/Q229/Q362/Q346/Q310/Q245/Q4
       Podophyllotoxin 0.5% cream8 (294)57/Q311/Q222/Q225/Q21/Q148/Q4
       Imiquimod 5%10 (611)57/Q313/Q250/Q326/Q213/Q324/Q3
       Polyphenon 15%3 (477)54/Q37/Q160/Q38/Q17/Q211/Q1
      Provider-administered without local anesthesia
       Trichloroacetic acid6 (334)72/Q214/Q226/Q217/Q28/Q218/Q2
       Cryotherapy12 (709)58/Q327/Q324/Q215/Q14/Q129/Q3
      Provider-administered with local anesthesia
       Surgery2 (48)92/Q120/Q2NR42/Q3NR48/Q4
       CO2 laser6 (329)88/Q131/Q457/Q343/Q30/Q110/Q1
       Electrosurgery3 (221)56
      Clearance was 79% after performing a per-protocol analysis of the data provided by Stone et al.
      • Stone K.M.
      • Becker T.M.
      • Hadgu A.
      • et al.
      Treatment of external genital warts: a randomised clinical trial comparing podophyllin, cryotherapy, and electrodesiccation.
      /Q3
      35/Q4NR8/Q1NR16/Q2
      AGW, Anogenital wart; HGL, high-grade local (blisters and ulcerations); ITT, intention-to-treat; LGG, low-grade general (pain requiring analgesics); LGL, low-grade local (stinging, irritation, erythema); MGL, medium-grade local (skin burn, soiling, minor bleeding, erosion, infection); NR, not reported; Q, quartile; RCT, randomized-controlled trial.
      First-line treatments mentioned in current international recommendations.
      • Gilson R.
      • Nugent D.
      • Werner R.N.
      • et al.
      2018 European guideline for the management of anogenital warts.
      Potassium hydroxide is not included in those guidelines, but our pooled-analysis results indicate that it could be.
      Outcomes are graded best (Q1) to worst (Q4) by quartile.
      Clearance was 79% after performing a per-protocol analysis of the data provided by Stone et al.
      • Stone K.M.
      • Becker T.M.
      • Hadgu A.
      • et al.
      Treatment of external genital warts: a randomised clinical trial comparing podophyllin, cryotherapy, and electrodesiccation.
      Although the risk of bias was high in many of the included studies (unpublished data), our results complement the latest guidelines.
      • Gilson R.
      • Nugent D.
      • Werner R.N.
      • et al.
      2018 European guideline for the management of anogenital warts.
      Therapies could be selected on the basis of anogenital wart duration and history of recurrence. Indeed, we found in our pooled analysis that recurrence at 12 months was lower for patient-administered treatments, making these more relevant than provider-administered therapies as a global therapeutic response—although such recurrence is difficult to evaluate because of the methodologic limitations (eg, lost to follow-up, recontamination). Although provider-administered therapies presented the best clearance before 3 months, their reproducibility remains difficult to compare both among RCTs and among treatments (eg, lack of standardization of freezing or surgical procedures). Given the need for local anesthesia, the use of surgery, CO2 laser, and electrosurgery seem justified when other treatments have failed. Last, knowledge of treatment side effects can assist physicians with adjusting anogenital wart management to the tolerance of the patient.
      We would like to thank Prof Rodolphe Thiebaut for his continuous support; our research librarian Evelyne Mouillet; the dermatologists of the French Group of Dermato-Infectiology and Sexually Transmitted Diseases of the Société Française de Dermatologie and the Association des Dermatologues des Alpes du Sud; and our copy editor Arianne Dorval.

      References

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        • Nugent D.
        • Werner R.N.
        • et al.
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        • Centers for Disease Control and Prevention
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        Date accessed: July 17, 2017
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        • Bouscarat F.
        • et al.
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        • et al.
        Treatment of external genital warts: a randomised clinical trial comparing podophyllin, cryotherapy, and electrodesiccation.
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