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NIHR Signal A commonly used surface treatment is the most suitable first-line treatment for genital warts

Published on 2 August 2016

doi: 10.3310/signal-000274

Podophyllotoxin 0.5% solution followed by carbon dioxide laser therapy only if unsuccessful may be the best treatment approach for anal and genital warts. Either of these treatments can successfully clear warts in over three quarters of people.

The podophyllotoxin 0.5% solution can be applied to the warts twice a day for three days at home. Further courses can be applied if necessary after a break of four days. Alternatively, carbon dioxide laser therapy is performed under local or general anaesthetic. Soreness and irritation is common after laser therapy but it is effective and also more useful for warts in less accessible places.

The results of this review suggest a potential first-line treatment strategy of podophyllotoxin 0.5% solution followed by carbon dioxide laser therapy if needed. This may simplify treatment selection, but in light of the limited evidence available, patient characteristics and preference are still likely to guide treatment. Current guidance from the British Association for Sexual Health and HIV recommends that treatment decisions are based upon factors such as gender and number of warts.

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Why was this study needed?

Anogenital warts are small growths caused by the human papillomavirus that appear in and around the genital or anal area. They are the second most common type of sexually transmitted infection in England, after chlamydia. In 2012, there were 73,893 new cases of genital warts diagnosed by sexual health clinics in England. In 2013, they accounted for 16 out of 100 new sexually transmitted infections.

Although usually painless, they can cause discomfort and distress. Warts may clear up without treatment, but the chances of this happening are uncertain. Delay may worsen the condition and increase the risk of transmission.

Several topical treatments such as creams and solutions are available, as are a range of physical removal options. However, about half of patients experience recurrence within one year, so repeat treatment is often required. This overview aimed to summarise the evidence of effectiveness and cost-effectiveness of treatments for anogenital warts.

What did this study do?

This systematic review included 60 randomised controlled trials and 41 economic evaluations of interventions to clear anogenital warts. Interventions included topical treatments, surgical removal, cryotherapy (freezing the wart) and carbon dioxide laser therapy. Treatments were compared using network meta-analysis, pooling not only direct evidence from “head-to-head” trials, but also comparing indirectly across trials.

An economic model was developed to determine cost-effectiveness at 58 weeks. This allowed for a treatment and follow-up period, and included first- and second-line treatments for persistent warts. A total of 84 treatment strategies were assessed.

Most studies were poorly reported and at unclear risk of bias. Despite identifying 60 effectiveness studies, most comparisons involved only single randomised controlled trials. Only nine studies were published within the last 10 years and study populations differed between trials. As such the results should be treated with some caution.  However further trials are unlikely to be possible and this study represents the most reliable evidence to guide treatment.

What did it find?

  • Carbon dioxide laser therapy was the most effective therapy with a 97.1% probability of achieving complete clearance by the end of treatment (95% credible interval (CrI) 84.8% to 99.9%).
  • Podophyllotoxin 0.5% solution was the second most effective therapy, with a complete clearance probability of 92.6% (95% CrI 81.8% to 98.4%).
  • Most other treatments improved the likelihood of complete clearance when compared with inactive placebo or no treatment with little difference in effectiveness between them.
  • Recurrence rates were lowest for carbon dioxide laser therapy and surgical excision but high for all treatments, ranging from 23.4% to 66.9% at up to six months, with no statistical differences between treatments.
  • Podophyllotoxin 0.5% solution as first-line treatment, followed by carbon dioxide laser therapy if required, had a probability of 80.7% of being the most cost-effective approach (at a willingness to pay of £20,000 to 30,000 per additional QALY gained). The next most cost-effective strategy was podophyllotoxin 0.5% solution followed by surgical removal but this was estimated to be over the willingness to pay threshold.
  • The estimated average cost per treatment strategy ranged from £199 (podophyllotoxin 0.5% solution followed by carbon dioxide laser therapy) to £700 (podophyllin 20 to 25% followed by cryotherapy) per patient.

What does current guidance say on this issue?

Current guidance produced by the British Association for Sexual Health and HIV provides examples of treatment algorithms for the management of anogenital warts in women and men. It recommends several treatments depending on shape, number, location and distribution of warts, as well as patient preference.

What are the implications?

Treatments that physically remove the warts, such as carbon dioxide laser therapy or surgical removal, may be a cost-effective option if used following the failure of cheaper topical treatments, such as podophyllotoxin 0.5% solution. These findings may help to inform decision making in clinical practice, given the wide range of treatments covered by current guidelines. However, patient characteristics, prior treatment history and preference are also likely to guide the most appropriate treatment option.

The uptake of HPV vaccination is likely to have an impact on the frequency of genital warts in the community and the main treatments for this condition appear to have high clearance rates at reasonable cost.

Citation and Funding

Thurgar E, Barton S, Karner C, Edwards SJ. Clinical effectiveness and cost-effectiveness of interventions for the treatment of anogenital warts: systematic review and economic evaluation. Health Technol Assess. 2016;20(24):1-486.

This project was funded by the National Institute for Health Research HTA programme (project number 12/44/01).

Bibliography

CKS. Warts – anogenital. London; National Institute for Health and Care Excellence: 2012.

Clinical Effectiveness Group. UK National Guidelines on the Management of Anogenital Warts 2015. Macclesfield: British Association for Sexual Health and HIV; 2015.

NHS Choices. Genital warts. London: NHS; 2014.

Why was this study needed?

Anogenital warts are small growths caused by the human papillomavirus that appear in and around the genital or anal area. They are the second most common type of sexually transmitted infection in England, after chlamydia. In 2012, there were 73,893 new cases of genital warts diagnosed by sexual health clinics in England. In 2013, they accounted for 16 out of 100 new sexually transmitted infections.

Although usually painless, they can cause discomfort and distress. Warts may clear up without treatment, but the chances of this happening are uncertain. Delay may worsen the condition and increase the risk of transmission.

Several topical treatments such as creams and solutions are available, as are a range of physical removal options. However, about half of patients experience recurrence within one year, so repeat treatment is often required. This overview aimed to summarise the evidence of effectiveness and cost-effectiveness of treatments for anogenital warts.

What did this study do?

This systematic review included 60 randomised controlled trials and 41 economic evaluations of interventions to clear anogenital warts. Interventions included topical treatments, surgical removal, cryotherapy (freezing the wart) and carbon dioxide laser therapy. Treatments were compared using network meta-analysis, pooling not only direct evidence from “head-to-head” trials, but also comparing indirectly across trials.

An economic model was developed to determine cost-effectiveness at 58 weeks. This allowed for a treatment and follow-up period, and included first- and second-line treatments for persistent warts. A total of 84 treatment strategies were assessed.

Most studies were poorly reported and at unclear risk of bias. Despite identifying 60 effectiveness studies, most comparisons involved only single randomised controlled trials. Only nine studies were published within the last 10 years and study populations differed between trials. As such the results should be treated with some caution.  However further trials are unlikely to be possible and this study represents the most reliable evidence to guide treatment.

What did it find?

  • Carbon dioxide laser therapy was the most effective therapy with a 97.1% probability of achieving complete clearance by the end of treatment (95% credible interval (CrI) 84.8% to 99.9%).
  • Podophyllotoxin 0.5% solution was the second most effective therapy, with a complete clearance probability of 92.6% (95% CrI 81.8% to 98.4%).
  • Most other treatments improved the likelihood of complete clearance when compared with inactive placebo or no treatment with little difference in effectiveness between them.
  • Recurrence rates were lowest for carbon dioxide laser therapy and surgical excision but high for all treatments, ranging from 23.4% to 66.9% at up to six months, with no statistical differences between treatments.
  • Podophyllotoxin 0.5% solution as first-line treatment, followed by carbon dioxide laser therapy if required, had a probability of 80.7% of being the most cost-effective approach (at a willingness to pay of £20,000 to 30,000 per additional QALY gained). The next most cost-effective strategy was podophyllotoxin 0.5% solution followed by surgical removal but this was estimated to be over the willingness to pay threshold.
  • The estimated average cost per treatment strategy ranged from £199 (podophyllotoxin 0.5% solution followed by carbon dioxide laser therapy) to £700 (podophyllin 20 to 25% followed by cryotherapy) per patient.

What does current guidance say on this issue?

Current guidance produced by the British Association for Sexual Health and HIV provides examples of treatment algorithms for the management of anogenital warts in women and men. It recommends several treatments depending on shape, number, location and distribution of warts, as well as patient preference.

What are the implications?

Treatments that physically remove the warts, such as carbon dioxide laser therapy or surgical removal, may be a cost-effective option if used following the failure of cheaper topical treatments, such as podophyllotoxin 0.5% solution. These findings may help to inform decision making in clinical practice, given the wide range of treatments covered by current guidelines. However, patient characteristics, prior treatment history and preference are also likely to guide the most appropriate treatment option.

The uptake of HPV vaccination is likely to have an impact on the frequency of genital warts in the community and the main treatments for this condition appear to have high clearance rates at reasonable cost.

Citation and Funding

Thurgar E, Barton S, Karner C, Edwards SJ. Clinical effectiveness and cost-effectiveness of interventions for the treatment of anogenital warts: systematic review and economic evaluation. Health Technol Assess. 2016;20(24):1-486.

This project was funded by the National Institute for Health Research HTA programme (project number 12/44/01).

Bibliography

CKS. Warts – anogenital. London; National Institute for Health and Care Excellence: 2012.

Clinical Effectiveness Group. UK National Guidelines on the Management of Anogenital Warts 2015. Macclesfield: British Association for Sexual Health and HIV; 2015.

NHS Choices. Genital warts. London: NHS; 2014.

Clinical effectiveness and cost-effectiveness of interventions for the treatment of anogenital warts: systematic review and economic evaluation

Published on 1 April 2016

Thurgar E, Barton S, Karner C, Edwards SJ.

Health Technology Assessment Volume 20 Issue 24 , 2016

Background Typically occurring on the external genitalia, anogenital warts (AGWs) are benign epithelial skin lesions caused by human papillomavirus infection. AGWs are usually painless but can be unsightly and physically uncomfortable, and affected people might experience psychological distress. The evidence base on the clinical effectiveness and cost-effectiveness of treatments for AGWs is limited. Objectives To systematically review the evidence on the clinical effectiveness of medical and surgical treatments for AGWs and to develop an economic model to estimate the cost-effectiveness of the treatments. Data sources Electronic databases (MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, The Cochrane Library databases and Web of Science) were searched from inception (or January 2000 for Web of Science) to September 2014. Bibliographies of relevant systematic reviews were hand-searched to identify potentially relevant studies. The World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov were searched for ongoing and planned studies. Review methods A systematic review of the clinical effectiveness literature was carried out according to standard methods and a mixed-treatment comparison (MTC) undertaken. The model implemented for each outcome was that with the lowest deviance information criterion. A de novo economic model was developed to assess cost-effectiveness from the perspective of the UK NHS. The model structure was informed through a systematic review of the economic literature and in consultation with clinical experts. Effectiveness data were obtained from the MTC. Costs were obtained from the literature and standard UK sources. Results Of 4232 titles and abstracts screened for inclusion in the review of clinical effectiveness, 60 randomised controlled trials (RCTs) evaluating 19 interventions were included. Analysis by MTC indicated that ablative techniques were typically more effective than topical interventions at completely clearing AGWs at the end of treatment. Podophyllotoxin 0.5% solution (Condyline®, Takeda Pharmaceutical Company Ltd; Warticon® solution, Stiefel Laboratories Ltd) was found to be the most effective topical treatment evaluated. Networks for other outcomes included fewer treatments, which restrict conclusions on the comparative effectiveness of interventions. In total, 84 treatment strategies were assessed using the economic model. Podophyllotoxin 0.5% solution first line followed by carbon dioxide (CO2) laser therapy second line if AGWs did not clear was most likely to be considered a cost-effective use of resources at a willingness to pay of £20,000–30,000 per additional quality-adjusted life-year gained. The result was robust to most sensitivity analyses conducted. Limitations Limited reporting in identified studies of baseline characteristics for the enrolled population generates uncertainty around the comparability of the study populations and therefore the generalisability of the results to clinical practice. Subgroup analyses were planned based on type, number and size of AGWs, all of which are factors thought to influence treatment effect. Lack of data on clinical effectiveness based on these characteristics precluded analysis of the differential effects of treatments in the subgroups of interest. Despite identification of 60 studies, most comparisons in the MTC are informed by only one RCT. Additionally, lack of head-to-head RCTs comparing key treatments, together with minimal reporting of results in some studies, precluded comprehensive analysis of all treatments for AGWs. Conclusions The results generated by the MTC are in agreement with consensus opinion that ablative techniques are clinically more effective at completely clearing AGWs after treatment. However, the evidence base informing the MTC is limited. A head-to-head RCT that evaluates the comparative effectiveness of interventions used in clinical practice would help to discern the potential advantages and disadvantages of the individual treatments. The results of the economic analysis suggest that podophyllotoxin 0.5% solution is likely to represent a cost-effective first-line treatment option. More expensive effective treatments, such as CO2 laser therapy or surgery, may represent cost-effective second-line treatment options. No treatment and podophyllin are unlikely to be considered cost-effective treatment options. There is uncertainty around the cost-effectiveness of treatment with imiquimod, trichloroacetic acid and cryotherapy. Funding The National Institute for Health Research Health Technology Assessment programme.

Genital warts are small fleshy growths, bumps or skin changes that appear on or around the genital or anal area. For more details see NHS Choices.

They are very common. In England, they are the second most common type of sexually transmitted infection after chlamydia. Genital warts are the result of a viral skin infection caused by the human papilloma virus (HPV). They are usually painless and do not pose a serious threat to health.

But they can be unpleasant to look at and cause psychological distress. There is no evidence that your fertility will be affected by genital warts.

HPV vaccines in the UK are offered to all girls in year 8 (aged 12 to 13 years).

Since September 2012, the vaccine Gardasil has been used and can help protect against HPV types 6 and 11, which cause around 90% of genital warts. It also protects against types 16 and 18, which are linked to more than 70% of cases of cervical cancer in the UK.

Expert commentary

There is limited evidence available to develop effective care pathways for the large number of people who have genital warts. First line therapy with topical podophyllotoxin is effective in clearing warts in a significant proportion of individuals but ablative therapies, to actually remove the wart tissue, should be not be delayed when the response is poor. Although head to head comparisons of wart treatments are lacking, these may be difficult to perform as the implementation of HPV vaccination in the UK is expected to reduce warts incidence substantially.

Jonathan Ross, Professor of Sexual Health and HIV, University Hospitals Birmingham NHS Foundation Trust