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BMJ Clin Evid. 2007; 2007: 1602.
Published online 2007 August 1.
PMCID: PMC2943795

Warts (genital)

Henry W. Buck, Jr, FACS, FACOG, Clinical Associate Professor of Obstetrics & Gynaecology, Courtesy Professor Health, Sports & Exercise Science, Lecturer in Pharmacy

Abstract

Introduction

External genital warts (EGWs) are sexually transmitted benign epidermal growths caused by the human papillomavirus (HPV), on the anogenital areas of both females and males. About 50-60% of sexually active women aged 18-49 have been exposed to HPV infection, but only 10-15% will have genital warts.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for external genital warts? What are the effects of interventions to prevent transmission of external genital warts? We searched: Medline, Embase, The Cochrane Library and other important databases up to February 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 47 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: bi- and trichloroacetic acid; condoms; cryotherapy; electrosurgery; imiquimod; intralesional, topical, or systemic interferons; laser surgery; podophyllin; podophyllotoxin; surgical excision; and vaccines.

Key Points

External genital warts (EGWs) are sexually transmitted benign epidermal growths caused by the human papillomavirus (HPV), on the anogenital areas of both females and males.

  • About 50-60% of sexually active women aged 18-49 have been exposed to HPV infection, but only 10-15% will have genital warts. Warts are more common in people with impaired immune systems, but, in people with adequate immune function, about a third can resolve spontaneously.
  • Some lesions, particularly those that are pigmented, should be biopsied to rule out severe dysplasia or melanoma, but external genital warts rarely, if ever, progress to cancer.

Imiquimod 1% and 5% creams increase clearance of warts compared with placebo in patients without HIV, but we don't know if they are effective in people with HIV.

  • Imiquimod 5% cream may be more likely to clear warts, but increases local irritation compared with 1% imiquimod cream.

Topical interferon increases wart clearance at 4 weeks compared with placebo.

  • Topical interferon is preferred to systemic interferon, which has not been shown consistently to be effective, is expensive to use, and is associated with severe side effects.
  • We don't know if intralesional interferon is effective, although it is time consuming and expensive to use.

Podophyllotoxin is more effective than placebo and probably as effective as podophyllin in clearing genital warts, but may be easier to use.

  • Podophyllin may contain mutagenic compounds, and its formulation is unstandardised, so podophyllotoxin is the preferred treatment, despite the risk of local burning and bleeding.

There is consensus that bi- and trichloroacetic acid and cryotherapy are effective treatments for external genital warts, although we found no studies comparing them to placebo.

Surgical (scissor) excision and electrosurgery may be effective at clearing genital warts at 6 months compared with no treatment, but we don't know whether laser surgery is also effective.

Vaccines are effective in preventing infection and disease by HPV in young women.

  • We don't know whether vaccines are effective in people other than young women.

We don't know whether condom use reduces the spread of HPV infection and genital warts.

About this condition

Definition

External genital warts (EGWs) are benign epidermal growths on the external anogenital regions. There are four morphological types: condylomatous, keratotic, papular, and flat warts. External genital warts are caused by the human papillomavirus (HPV). Diagnosis: The majority of external genital warts are diagnosed by inspection. Some clinicians apply 5% acetic acid (white vinegar) to help visualise lesions, because it produces so-called "acetowhite" change and, more importantly, defines vascular patterns characteristic for external genital warts. However, the "acetowhite" change also occurs with conditions other than external genital warts, so differential diagnoses should be considered. Some lesions, particularly those that are pigmented, should be biopsied to rule out severe dysplasia or melanoma.

Incidence/ Prevalence

In the USA in 2004, external genital warts accounted for more than 310,000 initial visits to private physicians’ offices. In the USA, 1% of sexually active men and women aged 18-49 are estimated to have external genital warts. It is believed that external and cervical lesions caused by HPV are the most prevalent sexually transmitted disease among people aged 18-25. In the USA, 50-60% of women aged 18-25 test positive for HPV DNA, but no more than 10-15% ever have genital warts. By the age of 50, at least 80% of women will have acquired genital HPV infection. About 6.2 million Americans acquire a new genital HPV infection each year.

Aetiology/ Risk factors

External genital warts are caused by HPV, and are sexually transmitted. They are more common in people with impaired immune function. Although more than 100 types of HPV have been identified, about a third of which are found in the anogenital regions, most external genital warts in immunocompetent people are caused by HPV types 6 and 11.

Prognosis

The ability to clear and remain free of external genital warts is a function of cellular immunity. In immunocompetent people, the prognosis in terms of clearance and avoiding recurrence is good; but people with impaired cellular immunity (e.g. people with HIV and AIDS) have great difficulty in achieving and maintaining wart clearance. Without treatment, external genital warts may remain unchanged, may increase in size or number, and about a third will clear. Clinical trials found that recurrences may happen, and may necessitate repeated treatment. External genital warts rarely, if ever, progress to cancer. Recurrent respiratory papillomatosis (RRP), a rare and sometimes life-threatening condition, occurs in children of women with a history of genital warts. Its rarity makes it difficult to design studies that can evaluate whether treatment in pregnant women alters the risk.

Aims of intervention

To eliminate warts from the external genitalia; to prevent recurrence; and to avoid sequelae, with minimal adverse effects.

Outcomes

Wart clearance, generally accepted as complete eradication of warts from the treated area, rather than elimination of HPV; recurrence; sequelae; adverse effects of treatment; quality of life; transmission. Although becoming HPV-negative is not a specific goal of treatment, the majority of people who have cleared lesions will become HPV DNA-negative.

Methods

BMJ Clinical Evidence search and appraisal February 2007.The following databases were used to identify studies for this review: Medline 1966 to February 2007, Embase 1980 to February 2007, and The Cochrane Database of Systematic Reviews 2006, Issue 2 to 2007 issue 1. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and National Institute for Health and Clinical Excellence (NICE) clinical guidelines. We also searched for retractions of studies in the review. Abstracts of the studies retrieved from the initial search were assessed independently by two information specialists. Selected studies were then sent to the author for initial assesment using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, at least single blinded, and containing more than 20 individuals of whom more than 80% were followed up. The minimum length of follow-up required to include studies was 6 months for preventive interventions. We excluded all studies described as ‘open’, ‘open-label’, or not blinded unless blinding was impossible. We also did a search for cohort studies on specific harms of named interventions. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are continually added to the review as required. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).

Table
GRADE evaluation of interventions for genital warts

Glossary

Electrosurgery
Includes any method in which an electrical current is used to transect or vaporise tissue, such as diathermy or electrocautery.
High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Very low-quality evidence
Any estimate of effect is very uncertain.

Notes

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Notes

Warts (non-genital)

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2007; 2007: 1602.
Published online 2007 August 1.

Imiquimod in people without HIV

Summary

WART CLEARANCE Compared with placebo: Imiquimod 1% or 5% increases wart clearance compared with placebo in people without HIV infection ( high-quality evidence ). 5% imiquimod compared with 1% imiquimod: 5% imiquimod is more effective than 1% imiquimod at clearing warts in people without HIV infection (high-quality evidence). WART RECURRENCE Compared with placebo: Imiquimod 5% may reduce wart recurrence after 10–16 weeks compared with placebo in people without HIV infection ( low-quality evidence ). 5% imiquimod compared with 1% imiquimod: 5% imiquimod is no more effective than 1% imiquimod at preventing recurrence of warts in people without HIV infection ( moderate-quality evidence ). ADVERSE EFFECTS Imiquimod is associated with moderate to severe erythema, erosion, excoriation, oedema, and scabbing. Higher doses are more likely than lower doses to cause adverse effects.

Benefits

Imiquimod versus placebo in people without HIV:

We found one systematic review (search date 2000, 5 RCTs in 588 people with genital warts without HIV infection) and two subsequent RCTs. The review found that, in people without HIV, imiquimod cream 1–5% significantly increased clearance rates over 16 weeks compared with placebo (5 RCTs; AR for clearance: 51% with imiquimod v 6% with placebo; RR 8.3, 95% CI 5.2 to 13.0; NNT 3, 95% CI 2 to 3). It found that imiquimod 1% or 5% significantly increased the proportion of people with complete clearance and no recurrence at 10–16 weeks after treatment compared with placebo (AR of clearance and no recurrence: 37% with imiquimod 5% v 15% with imiquimod 1% v 4–5% with placebo; RR for imiquimod 5% v placebo 9.0, 95% CI 4.9 to 17.0, NNT 3, 95% CI 3 to 4; RR for imiquimod 1% v placebo 2.9, 95% CI 1.5 to 5.9, NNT 10, 95% CI 3 to 91). In people whose warts completely cleared, recurrence during the 10–16 weeks after the end of the treatment was similar with imiquimod 1% and placebo, but higher with imiquimod 5% (3 RCTs; 18/112 [16%] with imiquimod 5% v 2/30 [7%] with imiquimod 1% v 1/13 [8%] with placebo; significance assessment not performed). The first subsequent RCT (60 men without HIV) found similar results (AR for clearance at 4 weeks: 70% with imiquimod 2% v 10% with placebo; P = 0.0001). The second subsequent RCT found that imiquimod 5% cream (3 times a week for 12 weeks) significantly increased the proportion of people with completely healed or improved genital warts compared with placebo (double blind RCT; 45 people without HIV, including 34 treated with imiquimod and 11 treated with placebo; method of measuring improvement unclear; AR for complete healing: 23/33 [70%] with imiquimod v 1/10 [10%] with placebo; AR for 50% to 90% improvement: 9/33 [27%] with imiquimod v 1/10 [10%] with placebo; AR for < 50% improvement: 1/33 [3%] with imiquimod v 8/10 [80%] with placebo; P < 0.01 for overall comparison between groups).

Different doses of imiquimod:

We found one systematic review (search date 2000) and one subsequent RCT. The review identified two RCTs, which compared 5% imiquimod cream, 1% imiquimod cream, and placebo. The first RCT identified by the review found that 5% imiquimod cream significantly increased wart clearance compared with 1% imiquimod cream (279 people without HIV; 49/94 [52%] with 5% imiquimod cream v 13/90 [14%] 1% imiquimod cream; P < 0.0001). Recurrence rates in people who had complete wart clearance were similar in both groups after 12 weeks' follow up (9/48 [19%] with 5% imiquimod cream v 2/12 [17%] with 1% imiquimod cream; significance assessment not performed). The second RCT identified by the review also found that 5% imiquimod cream significantly increased wart clearance compared with 1% imiquimod cream (311 people without HIV; 54/109 [49%] with 5% imiquimod cream v 21/102 [21%] with 1% imiquimod cream; P < 0.001). It found no significant difference in recurrence after 12 weeks' follow-up (6/45 [13%] with 5% imiquimod cream v 0/18 [0%] with 1% imiquimod cream; difference reported as not significant, P value not reported).

Harms

Imiquimod versus placebo:

The systematic review found no significant difference between imiquimod and placebo in withdrawal from treatment because of adverse effects (4 RCTs; AR 1.8% with imiquimod v 0% with placebo; RR 1.7, 95% CI 0.4 to 9.9). The largest included RCT found that moderate to severe erythema, erosion, excoriation, oedema, and scabbing were more common with imiquimod 5% than with placebo, but occurred with similar frequency in the imiquimod 1% and placebo groups (erythema: 40% with imiquimod 5% v 4% with imiquimod 1% v 3% with placebo; erosion: 10% with imiquimod 5% v 1% with imiquimod 1% v 2% with placebo; excoriation: 7% with imiquimod 5% v 0% with imiquimod 1% v 0% with placebo; oedema: 2% v 0% v 0%; scabbing: 5% with imiquimob 5% v 2% with imiquimod 1% v 0% with placebo; significance assessments not performed). The first subsequent RCT found that 18% of people taking imiquimod had mild erythema, erosion, or oedema. The second subsequent RCT found no withdrawals caused by adverse effects. It found that imiquimod 5% increased the proportion of people reporting any adverse effects, erythema, and erosion compared with placebo, but the statistical significance of these differences was not reported (any adverse effect: 18/33 [54%] with imiquimod v 4/10 [40%] with placebo; erythema and erosion: 6/33 [18%] with imiquimod v 0/10 [0%] with placebo; moderate or mid-severity erythema: 7/33 [21%] with imiquimod v 0/10 [0%] with placebo; significance assessments not performed).

Different doses of imiquimod:

The first RCT identified by the review found that more people had itching, pain, and burning at the application site with 5% imiquimod cream than with 1% imiquimod cream (itching: 33% with imiquimod 5% v 23% with imiquimod 1%; pain: 35% with imiquimod 5% v 13% with imiquimod 1%; burning: 16% with imiquimod 5% v 14% with imiquimod 1%; significance assessments not performed for dose comparisons). Similar proportions of people in each group discontinued treatment because of adverse events (1% in both groups). The second RCT identified by the review found that moderate to severe erythema, erosion, excoriation, oedema, and scabbing were more common with imiquimod 5% than with imiquimod 1% (erythema: 40% with imiquimod 5% v 4% with imiquimod 1%; erosion: 10% with imiquimod 5% v 1% with imiquimod 1%; excoriation: 7% with imiquimod 5% v 0% with imiquimod 1%; oedema: 2% with imiquimod 5% v 0% with imiquimod 1%; scabbing: 5% with imiquimod 5% v 2% with imiquimod 1%; significance assessments not performed). The subsequent RCT found that imiquimod twice daily significantly increased the proportion of people with severe erythema compared with imiquimod once daily or three times weekly (25% with twice daily v 10% with once daily v 4% with 3 times weekly; P = 0.01).

Comment

A secondary analysis of one of the RCTs identified by the review (209 people without HIV) found that imiquimod significantly increased wart clearance compared with placebo, regardless of gender, initial wart size, duration of current outbreak of warts, previous wart treatment, and tobacco use of participants.

Clinical guide:

Imiquimod acts by increasing the body's immune response. Most people tolerate treatment well.

Substantive changes

No new evidence

2007; 2007: 1602.
Published online 2007 August 1.

Imiquimod in people with HIV

Summary

WART CLEARANCE Compared with placebo: Imiquimod 5% cream seems no more effective at clearing warts after 16 weeks than placebo in people with HIV infection ( moderate-quality evidence ).

Benefits

We found one systematic review (search date 2000; 1 RCT, 100 people with HIV). The RCT identified by the review found no significant difference in clearance at 16 weeks between imiquimod cream 5% and placebo (11% with imiquimod v 6% with placebo; P = 0.48).

Harms

See harms of imiquimod in people without HIV.

Comment

See comment on imiquimod in people without HIV.

Substantive changes

No new evidence

2007; 2007: 1602.
Published online 2007 August 1.

Interferon (topical)

Summary

WART CLEARANCE Compared with placebo: Topical interferon increases wart clearance compared with placebo after 4 weeks ( moderate-quality evidence ). Compared with podophyllotoxin: Topical interferon increases wart clearance after 4 weeks compared with podophyllotoxin (moderate-quality evidence). NOTE We found no clinically important results about the effects of topical interferon compared with other treatments.

Benefits

We found no systematic review.

Topical interferon versus placebo:

We found three RCTs. The RCTs found that interferon significantly increased complete wart clearance 4 weeks after treatment compared with placebo (first RCT, 89 people; AR for wart clearance: 6% with interferon v 3% with placebo, CI not reported; second RCT, 60 women; AR for wart clearance: 73% with interferon v 10% with placebo, P < 0.0001; third RCT, 60 women; AR for wart clearance: 90% with interferon v 20% with placebo, CI not reported; see comment below). About a third of people in each group in the first RCT had cleared their warts by 16 weeks. Recurrence rates were not evaluated.

Topical interferon versus podophyllotoxin:

One of the RCTs also compared topical interferon versus podophyllotoxin. It found that topical interferon significantly increased wart clearance at 4 weeks after treatment compared with podophyllotoxin (18/20 [90%] with topical interferon v 12/20 [60%] with podophyllotoxin; P = 0.0285).

Topical interferon versus other treatments:

We found no RCTs.

Harms

Topical interferon versus placebo:

One RCT reported local burning and itching in 39% of people using topical interferon. The RCT did not report harms for the no-treatment group. The second RCT reported that there were only mild adverse effects. The third RCT did not report on harms.

Topical interferon versus podophyllotoxin:

The RCT reported fever, headache, and itching in 18% of people using topical interferon over 16 weeks.

Topical interferon versus other treatments:

We found no RCTs.

Comment

Topical interferon versus placebo:

Clinical guide:

Topical interferon is not widely available.

Substantive changes

No new evidence

2007; 2007: 1602.
Published online 2007 August 1.

Podophyllotoxin

Summary

CLEARANCE OF WARTS Compared with placebo: Podophyllotoxin is more effective than placebo at clearing genital warts after 16 weeks ( high-quality evidence ). Compared with topical interferon: Podophyllotoxin is less effective than topical interferon at clearing genital warts after 4 weeks ( moderate-quality evidence ). Compared with podophyllin: Podophyllotoxin seems to be as effective as podophyllin at clearing genital warts ( moderate quality evidence ).

Benefits

We found no systematic review.

Podophyllotoxin versus placebo:

We found eight RCTs (1035 people) comparing podophyllotoxin versus placebo. All found that, within 16 weeks of treatment, podophyllotoxin was more effective for clearance than placebo (RRs of clearance v placebo ranged between 2.0 [95% CI 0.9 to 4.3] and 48.0 [95% CI 3 to 773]). RCTs of 0.5% cream or solution found recurrence rates ranging from 4% to 33%. One RCT (57 people) of 0.5% podophyllotoxin solution as prophylaxis against recurrence of external genital warts (initially treated in an open label study) found fewer recurrences among people taking placebo.

Podophyllotoxin versus interferon, topical:

See benefits of interferon, topical.

Podophyllotoxin versus podophyllin:

We found six RCTs comparing podophyllotoxin versus podophyllin. Five RCTs found no significant difference in wart clearance (RR values for podophyllin v podophyllotoxin ranging between 0.7 [95% CI 0.4 to 1.1] and 1.7 [95% CI 0.9 to 3.2]). One of these RCTs used a 2% podophyllin solution in a limited study of self-treatment for penile warts, and found no significant difference in clearance between podophyllotoxin and podophyllin (RR for podophyllin v podophyllotoxin 0.6, 95% CI 0.3 to 1.3). The sixth RCT (358 immunocompetent men and women with genital warts for 3 months or less, 276 [77%] completed) compared podophyllotoxin (self-treatment with 0.5% solution or 0.15% cream twice daily for 3 days with 4 days off) versus podophyllin (25% applied twice weekly at a clinic). Both treatments were given until warts were cleared, up to a maximum of 4 weeks. The RCT found that podophyllotoxin solution, but not podophyllotoxin cream, significantly increased complete remission of warts at 4 weeks compared with podophyllin (intention to treat analysis: OR 1.92, 95% CI 1.13 to 3.27 for solution; OR 1.17, 95 % CI 0.69 to 2.00 for cream). It found no significant difference between treatments in recurrence of warts at 12 weeks among those with initial clearance (74 people analysed: 15/33 [45%] with podophyllotoxin solution v 12/22 [54%] with podophyllotoxin cream v 5/19 [26%] with podophyllin; P reported as not significant). High withdrawal, and the potential for selection bias among returning people, limit the reliability of these results.

Harms

Cohort studies have reported rare cases of balanoposthitis. Safety during pregnancy is unknown.

Podophyllotoxin versus placebo:

Local inflammation or irritation, erosion, burning, pain, and itching are reported in most trials. Dyspareunia, bleeding, scarring, and insomnia are reported rarely.

Podophyllotoxin versus interferon, topical:

See harms of interferon, topical.

Podophyllotoxin versus podophyllin:

One large RCT reported burning and inflammation in 75%, and bleeding in 25% of people treated with podophyllotoxin. Six RCTs reported pain, erythema, irritation, and tenderness in 3–17% of people treated with podophyllin. Skin burns (1–3%), bleeding (4%), and erosion or ulcerations (1% to 11%) were also reported. Faecal incontinence (4%) and preputial tightening (1%) were reported rarely. One RCT found that podophyllotoxin solution increased local adverse effects and ulceration compared with podophyllotoxin cream and podophyllin (local effects: 33% with podophyllotoxin solution v 24% with podophyllotoxin cream v 17% with podophyllin; ulceration: 18% v 12% v 10%; P values not reported).

Comment

RCTs examined the efficacy of podophyllotoxin solutions more often than cream preparations, but cream or gel preparations may be easier to apply than solutions. This and other differences may cause variable efficacy. Podophyllotoxin does not contain the mutagenic flavonoid compounds quercetin and kaempherol, which are contained in podophyllin resin preparations.

Clinical guide:

Podophyllotoxin is the main active ingredient of podophyllin resin that has been purified and prepared to a well standardised concentration. It can be used in an office setting or by the person at home. Because of its purity and ease of use, podophyllotoxin is to be preferred over podophyllin.

Substantive changes

No new evidence

2007; 2007: 1602.
Published online 2007 August 1.

Bi- and trichloroacetic acid

Summary

WART CLEARANCE Compared with cryotherapy: Trichloroacetic acid is as effective as cryotherapy at clearing genital warts after 6–10 weeks ( high-quality evidence ). WART RECURRENCE Compared with cryotherapy: Trichloroacetic acid is as effective as cryotherapy at preventing wart recurrence 2 months after the end of treatment ( moderate-quality evidence ). NOTE We found no direct information about whether or not bi- and trichloroacetic acid are better than no active treatment, or about their effects compared with other treatments. There is clinical consensus that bi- and trichloroacetic acid are effective for clearing genital warts.

Benefits

We found no systematic review.

Bi- and trichloroacetic acid versus placebo:

We found no RCTs.

Trichloroacetic acid versus cryotherapy:

Two RCTs found no significant difference between trichloroacetic acid and cryotherapy in wart clearance after 6 or 10 weeks of treatment (6 weeks, 1 RCT, 86 people: 21/33 [64%] with trichloroacetic acid v 37/53 [70%] with cryotherapy, RR 0.91, 95% CI 0.67 to 1.25; 10 weeks, 1 RCT, 130 men: 43/49 [88%] with trichloroacetic acid v 46/57 [81%] with cryotherapy, RR 1.08, 95% CI 0.92 to 1.24). One of the RCTs found no significant difference in recurrence at 2 months after the end of 10 weeks of treatment (14/39 [36%] with trichloroacetic acid v 15/38 [39%] with cryotherapy; RR 0.91, 95% CI 0.51 to 1.61).

Trichloroacetic acid versus other treatments:

We found no RCTs.

Bichloroacetic acid versus other treatments:

We found no RCTs.

Harms

Safety during pregnancy is unknown.

Bi- and trichloroacetic acid versus placebo:

We found no RCTs.

Trichloroacetic acid versus cryotherapy:

The first RCT gave no information on adverse effects. The second RCT found no significant difference in discomfort, ulceration, and scabbing between cryotherapy and trichloroacetic acid (29/57 [51%] with trichloroacetic acid v 19/43 [44%] with cryotherapy; reported as non-significant, CI not reported).

Comment

Small numbers of people and inadequate study designs make it difficult to evaluate effectiveness. In pregnant women, only case series are available; in one case series, 31/32 (97%) pregnant women treated with trichloroacetic acid had wart clearance, and 2/31 (6%) had recurrence.

Clinical guide:

These compounds are relatively inexpensive and widely used. Minimal training is required for practitioners to use them. Care must be exercised to avoid application to normal tissue adjacent to the wart tissue. Treated sites may be quite painful for some hours after application.

Substantive changes

No new evidence

2007; 2007: 1602.
Published online 2007 August 1.

Cryotherapy

Summary

WART CLEARANCE Compared with trichloroacetic acid: Cryotherapy is as effective as trichloroacetic acid at clearing genital warts after 6–10 weeks ( high-quality evidence ). Compared with electrosurgery: Cryotherapy is as effective as electrosurgery at clearing genital warts after 3 months ( moderate-quality evidence ). WART RECURRENCE Compared with trichloroacetic acid: Cryotherapy is as effective as trichloroacetic acid at preventing wart recurrence 2 months after the end of treatment (moderate-quality evidence). NOTE We found no direct information about whether cryotherapy is better than no active treatment, or about its effects compared with other treatments. There is clinical consensus that cryotherapy is effective for clearing genital warts.

Benefits

We found no systematic review.

Cryotherapy versus placebo:

We found no RCTs comparing cryotherapy versus placebo or no treatment.

Cryotherapy versus bi- and trichloroacetic acid:

See benefits of bi- and trichloroacetic acid.

Cryotherapy versus electrosurgery:

We found one RCT. The RCT (42 people) compared cryotherapy versus electrosurgery given at 2-weekly intervals as necessary until warts were completely cleared. It found no significant difference in wart clearance at 3 months' follow-up between cryotherapy and electrosurgery (10/18 [566%] with cryotherapy v 10/24 [42%] with electrosurgery; RR 1.33, 95% CI 0.71 to 2.50).

Cryotherapy versus other treatments:

We found no good quality RCTs.

Harms

Cryotherapy versus placebo:

We found no RCTs. One case series of 34 pregnant women who received three or fewer treatments of cryotherapy found no subsequent infection or premature rupture of membranes.

Cryotherapy versus bi- and trichloroacetic acid:

See harms of bi- and trichloroacetic acid.

Cryotherapy versus other treatments:

We found no good-quality RCTs.

Comment

Clinical guide:

There is clinical consensus that cryotherapy is likely to be beneficial for clearance of genital warts. There are at least three different methods of delivering cryotherapy: using a cryotherapy probe in a cryotherapy unit; using a cotton-tipped applicator dipped in a coolant such as liquid nitrogen; or spraying directly with a liquefied gas such as liquid nitrogen. Minimal training is required for practitioners to be able to apply these treatments. There is usually only mild pain after treatment.

Substantive changes

No new evidence

2007; 2007: 1602.
Published online 2007 August 1.

Electrosurgery

Summary

WART CLEARANCE Compared with no treatment: Electrosurgery increases clearance of genital warts compared with no treatment ( high-quality evidence ). Compared with cryotherapy: Electrosurgery is as effective as cryotherapy at clearing genital warts after 3 months ( moderate-quality evidence ). Compared with systemic interferon: Electrosurgery may be as effective as intramuscular or subcutaneous interferon at clearing genital warts after 6 months (moderate-quality evidence). WART RECURRENCE Compared with systemic interferon: Electrosurgery may be more effective than intramuscular or subcutaneous interferon at preventing recurrence of warts after 6 months, but the benefit may not persist for longer than this (moderate-quality evidence). NOTE We found no clinically important results about the effects of electrosurgery compared with other treatments.

Benefits

We found no systematic review.

Electrosurgery versus no treatment or sham treatment:

We found one RCT (203 women), which compared four treatments: electrosurgery (diathermy); intramuscular or subcutaneous recombinant interferon alfa-2b; and no treatment. It found that electrosurgery significantly increased clearance of warts at 6 months after treatment compared with no treatment (82% with electrosurgery v 8% with no treatment; P < 0.001).

Electrosurgery versus cryotherapy:

See benefits of cryotherapy.

Electrosurgery versus interferon (systemic):

The RCT (203 women) comparing four treatments (see electrosurgery versus no treatment or sham treatment above) found that electrosurgery increased clearance of warts at 6 months compared with interferon but the increase was not significant (see table 1 ). Interferon significantly reduced recurrence rates at 6 months, but not at 12 months, compared with electrosurgery.

Table 1
RCTs of systemic interferon in people with genital warts.

Electrosurgery versus other treatments:

We found no good quality RCTs.

Harms

Electrosurgery versus no treatment:

One RCT (203 women) found that the most common adverse effect after electrosurgery was slow cicatrisation, present in 9/51(18 %) people, and lasting for 30–50 days. Other adverse effects after electrosurgery included moderate local oedema and pain (17/51 [33%]), and dyspareunia (2/51 [4%]), which lasted from 1–8 weeks (median 2 weeks). No comparison versus the no treatment group was presented.

Electrosurgery versus interferon, systemic:

The RCT did not directly compare adverse effects between electrosurgery and interferon (see table 1 ). See also harms of interferon, systemic.

Electrosurgery versus other treatments:

We found no good quality RCTs.

Comment

Clinical guide:

Equipment and training are required to perform electrosurgery. Slow cicatrisation may occur, and treatment can be painful.

Substantive changes

No new evidence

2007; 2007: 1602.
Published online 2007 August 1.

Podophyllin

Summary

WART CLEARANCE Compared with podophyllotoxin: Podophyllin seems as effective as podophyllotoxin at clearing genital warts ( moderate-quality evidence ). Compared with systemic interferon: Podophyllin is more effective than intramuscular or subcutaneous interferon at clearing genital warts after 3 months (moderate-quality evidence). Comapred with surgical excision: Podophyllin is as effective as surgical excision at clearing genital warts (moderate-quality evidence). Different doses of podophyllin: Podophyllin 10% is as effective as podophyllin 25% at clearing warts in men with anogenital warts (moderate-quality evidence). WART RECURRENCE Compared with surgical excision: Podophyllin is less effective than surgical excision at preventing recurrence of genital warts after 6–12 months (moderate-quality evidence). ADVERSE EFFECTS Podophyllin, unlike pdophyllotoxin, may contain the mutagenic flavonoid compounds quercetin and kaempherol. NOTE We found no direct information about whether podophyllin is better than no active treatment, or whether it is more effective than cryotherapy. There is consensus that podophyllin is effective for clearing genital warts.

Benefits

We found no systematic review.

Podophyllin versus placebo:

We found no RCTs.

Different doses of podophyllin:

One RCT (140 men with anogenital warts) found no significant difference in clearance rates at 3 months between podophyllin 10% and podophyllin 25% (AR 22% in both groups).

Podophyllin versus cryotherapy:

We found no good RCTs.

Podophyllin versus interferon, systemic:

See benefits of interferon, systemic.

Podophyllin versus podophyllotoxin:

See benefits of podophyllotoxin.

Podophyllin versus surgical excision:

See benefits of surgical excision.

Harms

Safety during pregnancy is unknown.

Different doses of podophyllin:

The RCT stated that podophyllin 10% or 25% was not associated with hypersensitivity or ulceration.

Podophyllin versus cryotherapy:

We found no good RCTs.

Podophyllin versus electrosurgery:

See harms of electrosurgery.

Podophyllin versus interferon, systemic:

See harms of interferon, systemic.

Podophyllin versus podophyllotoxin:

See harms of podophyllotoxin.

Podophyllin versus surgical excision:

See harms of surgical excision.

Comment

Clinical guide:

There is clinical consensus that podophyllin is likely to be beneficial for the clearance of genital warts. Podophyllin may contain the mutagenic flavonoid compounds quercetin and kaempherol. In addition to the mutagenic compounds contained in podophyllin, because it is a natural product, concentrations of the active ingredient are not standardised. If this form of treatment is to be used, podophyllotoxin is preferable.

Substantive changes

No new evidence

2007; 2007: 1602.
Published online 2007 August 1.

Surgical excision

Summary

WART CLEARANCE Compared with podophyllin: Surgical excision is as effective as podophyllin at clearing genital warts ( moderate-quality evidence ). Compared with laser surgery: Surgical excision is as effective as laser surgery at clearing genital warts (moderate-quality evidence). WART RECURRENCE Compared with podophyllin: Surgical excision of warts is more effective than podophyllin at preventing recurrence after 6–12 months (moderate-quality evidence). Compared with laser surgery: Surgical excision is as effective as laser surgery at preventing recurrence of genital warts (moderate-quality evidence). ADVERSE EFFECTS Surgical excision of external genital warts can cause significant pain. NOTE We found no direct information about whether surgical excision is better than no active treatment, or about its effects compared with other treatments.

Benefits

We found no systematic review.

Surgical excision versus no treatment:

We found no RCTs comparing surgical excision versus no treatment.

Surgical excision versus laser surgery:

We found one RCT comparing surgical excision versus carbon dioxide laser. It found no significant difference in clearance between laser and surgical excision (43 people; RR 1.2, 95% CI 0.6 to 2.4), and no significant difference in recurrence rates between the two treatments.

Surgical excision versus podophyllin:

We found two RCTs (97 people). They found no significant difference between surgical excision and podophyllin in wart clearance (16/18 [89%] with surgical excision v 15/19 [79%] with podophyllin; RR 1.13, 95% CI 0.85 to 1.50; 28/30 [93%] with surgical excision v 23/30 [77%] with podophyllin; P = 0.20). However, they found that surgical excision significantly reduced recurrence rates over 6–12 months compared with podophyllin (19% with surgical excision v 60% with podophyllin, P = 0.05; 29% with excision v 65% with podophyllin, P < 0.01).

Surgical excision versus other treatments:

We found no RCTs.

Harms

All surgically treated people experienced pain.

Surgical excision versus laser surgery:

The RCT found no significant difference in scar formation between surgical excision and laser surgery, although fewer people having surgical excision developed scars (9% had scars with surgical excision v 28% with laser surgery; P > 0.2). Postoperative pain was reported equally in both groups.

Surgical excision versus podophyllin:

Both RCTs found that more people receiving surgical excision than receiving podophyllin had pain (11/18 [61%] with excision v 5/19 [26%] with podophyllin; 25/30 [83%] with excision v 7/30 [23%] with podophyllin). The second RCT also found that more people receiving surgical excision than receiving podophyllin had bleeding (13/30 [43%] with excision v 11/30 [37%] with podophyllin). The RCTs did not assess the significance of the differences between groups.

Comment

Clinical guide:

Surgical excision of external genital warts can cause significant pain, and treatment is more resource-intensive and expensive than applying topical preparations.

Substantive changes

No new evidence

2007; 2007: 1602.
Published online 2007 August 1.

Interferon (intralesional)

Summary

We found no clinically important results about the effects of interlesional interferon in people with genital warts.

Benefits

We found no systematic review or RCTs that assessed interlesional interferon.

Harms

We found no RCTs.

Comment

Clinical guide:

Interlesional interferon has found little acceptance among clinicians, and is rarely used. It is time-consuming to use and expensive.

Substantive changes

No new evidence

2007; 2007: 1602.
Published online 2007 August 1.

Laser surgery

Summary

WART CLEARANCE Compared with surgical excision: Laser surgery is as effective as surgical excision at clearing genital warts ( moderate-quality evidence ). WART RECURRENCE Compared with surgical excision: Laser surgery is as effective as surgical excision at preventing recurrence of genital warts (moderate-quality evidence). ADVERSE EFFECTS Laser surgery has been associated with serious adverse effects. NOTE We found no direct information about whether laser surgery is better than no active treatment, or about its effects compared with other treatments.

Benefits

We found no systematic review.

Laser surgery versus no treatment:

We found no RCTs comparing laser surgery versus no treatment.

Laser surgery versus surgical excision:

See benefits of surgical excision.

Laser surgery versus other treatments:

We found no RCTs.

Harms

Laser surgery versus no treatment:

We found no RCTs.

Laser surgery versus surgical excision:

See harms of surgical excision.

Laser surgery versus other treatments:

We found no RCTs.

Comment

Clinical guide:

At one time, laser surgery was thought to be the solution for treatment of external genital warts. However, it is becoming less frequently used, because it has not been proven to be superior to other methods, there is a risk of serious complications in relatively inexperienced hands, and it requires expensive equipment.

Substantive changes

No new evidence

2007; 2007: 1602.
Published online 2007 August 1.

Interferon (systemic)

Summary

WART CLEARANCE Compared with placebo: The effects of systemic interferon compared with placebo in people with genital warts are unclear ( moderate-quality evidence ). Compared with podophyllin: Systemic interferon is less effective than podophyllin at clearing genital warts after 3 months (moderate-quality evidence). Compared with electrosurgery: Intramuscular or subcutaneous interferon may be as effective as electrosurgery at clearing genital warts after 6 months (moderate-quality evidence). Different preparations of systemic interferon: No one preparation of interferon is more effective at clearing genital warts than the others ( high-quality evidence ). WART RECURRENCE Compared with electrosurgery: Intramuscular or subcutaneous interferon may be less effective than electrosurgeryat preventing recurrence of warts after 6 months, but the benefit may not persist for longer than this (moderate-quality evidence). ADVERSE EFFECTS Systemic interferon is associated with important adverse effects, including anaphylaxis, blood disorders, flu-like symptoms, headache, fatigue, myalgia, fever, and weight loss.

Benefits

We found no systematic review.

Systemic interferon versus placebo or no treatment:

We found five RCTs, which compared different formulations of systemic interferon versus placebo or no treatment (see table 1 ). Two RCTs found that interferon significantly increased wart clearance compared with placebo or no treatment. Three RCTs found no significant difference between interferon and placebo in complete or partial (at least 75% reduction in lesion area) wart clearance. One study found that treatment with pegylated interferon alfa-2b was effective in HIV-positive patients compared with no treatment, with added concomitant positive effects on the suppression of HIV-1 replication and CD4 cell count.

Systemic interferon versus electrosurgery:

See benefits of electrosurgery.

Systemic interferon versus podophyllin:

One RCT (154 people with condylomata acuminata of< 6 months' duration) found that systemic interferon was significantly less effective that podophyllin in clearing warts at 3 months (AR for clearance: 23% with interferon v 45% with podophyllin; P = 0.003).

Different preparations of interferon:

Three RCTs compared different interferon preparations versus each other, and found no consistent differences between preparations (see table 1 ).

Harms

Systemic interferon versus placebo or no treatment:

Two RCTs reported that adverse effects were more common with interferon than with placebo. However, the significance of this difference was not always reported (see table 1 ). Two RCTs found similar incidences of adverse effects in the interferon and placebo groups, and one RCT did not report on adverse effects in the no-treatment group. The most common adverse effect with interferon was flu-like symptoms, which occurred in between 2% and 100% of participants (see table 1 ). Other adverse effects commonly observed with interferon included headache, fatigue, malaise, myalgia, fever, neuropsychiatric symptoms (drowsiness, lethargy, or confusion), and weight loss, which occurred in 6–96% of participants. Anaphylactic reaction occurred in 2% of people receiving intramuscular interferon in one RCT; another RCT reported leukopenia in 6% of people, thrombocytopenia in 4% of people, and raised liver enzymes in 8% of people. One open-label dose–response study also found raised liver enzymes with intramuscular interferon gamma.

Systemic interferon versus electrosurgery:

See harms of electrosurgery.

Different preparations of interferon:

Three RCTs compared different interferon preparations versus each other (see table 1 ). One RCT found that subcutaneous interferon significantly increased neuropsychiatric problems (drowsiness, lethargy, or confusion) and headache compared with intramuscular interferon (see table 1 ). One RCT found that a higher dose (9 MIU) of interferon significantly increased flu-like symptoms compared with a lower dose (3 MIU) (see table 1 ). One RCT compared three different preparations of interferon versus placebo, but did not compare harms of the interferon regimens.

Comment

Clinical guide:

Interferon forms part of the body's response to external genital warts, hence the rationale for its use. The adverse effects of systemic interferon can be quite disturbing to the individual. Unfortunately, systemic interferon has not fulfilled expectations of its potential benefits. This, combined with its considerable expense, has led most clinicians to not use it.

Substantive changes

No new evidence

2007; 2007: 1602.
Published online 2007 August 1.

Condoms

Summary

PREVALENCE OF HUMAN PAPILLOMAVIRUS Compared with no condom use: Regular use of condoms may not reduce the prevalence of HPV infection compared with no condom use ( very low-quality evidence ). PREVALENCE OF GENITAL WARTS Compared with no condom use: Regular use of condoms may reduce the prevalence of genital warts compared with no condom use (very low-quality evidence). NOTE Penetrative intercourse is not required for spread, because this can occur with external genital–genital or hand–genital touching.

Benefits

We found one systematic review (search date 2000, 1 cohort, 2 cross-sectional, 5 case control studies) comparing the effects of condom use versus no or occasional condom use on transmission of subclinical human papillomavirus (HPV), or transmission of external genital warts. The review could not perform a meta-analysis because of heterogeneity of populations in the studies retrieved. The review was unable to draw firm conclusions about the effects of condom use on transmission of HPV, but suggested that condom use may reduce the risk of developing external genital warts. It identified six studies (479 women) assessing the effects of condom use on transmission of subclinical HPV, one of which found that condom use reduced the incidence of HPV. One cross-sectional study (182 women sex workers) identified by the review found that women who always used condoms were significantly less likely to have HPV than women who occasionally or never used condoms (OR 0.2, 95% CI 0.1 to 0.6). However, two case-control studies and one cohort study (2638 women) found no significant difference between regular condom use and no use in the proportion of women who had HPV. Another two case control studies (1659 women) found that women who always used condoms were significantly more likely to have HPV than women who never used them (OR 3.8, 95% CI 1.2 to 11.6 in the first study; OR 1.5, 95% CI 1.1 to 2.0 in the second). One cross-sectional study (432 male military recruits) identified by the review found that men who always used condoms were significantly less likely to have genital warts or HPV than men who occasionally or never used condoms (OR 0.3, 95% CI 0.2 to 0.5). One case-control study (1298 people attending a sexually transmitted disease clinic) also found that people who always used condoms were significantly less likely to have genital warts than people who never used them (adjusted OR for men 0.3, 95% CI 0.2 to 0.4; adjusted OR for women 0.6, 95% CI 0.4 to 0.9). There is indirect evidence from an RCT using condoms as part of treatment in women with cervical intraepithelial neoplasia suggesting that condoms may have a clinical impact on transmission (see comment below).

Harms

The review gave no information on adverse effects.

Comment

Penetrative intercourse is not required for spread, because this can occur with external genital–genital or hand–genital touching. It is believed that, for transmission, the virus must be in the form of a virion, which occurs only in lesions. Viable transmission does not occur with contact with the HPV without a lesion. One RCT identified women with cervical intraepithelial neoplasia, and randomised couples to regular use of condoms or no condoms. The RCT reported separately the outcomes in women and in men. Regular condom use in women with cervical intraepithelial neoplasia was associated with an improved 2-year cumulative regression rate (53% with regular condom use v 35% with no condom use; P = 0.03). Among their male partners, condoms were associated with shortened median time to regression of flat penile lesions (7.4 months with regular condom use v 13.9 months with no condom use; HR 2.1, 95% CI 1.2 to 3.7). This effect was not found for papular lesions.

Substantive changes

No new evidence

2007; 2007: 1602.
Published online 2007 August 1.

Vaccines

Summary

HUMAN PAPILLOMAVIRUS INFECTION RATES Compared with placebo: Quadrivalent vaccine reduces the risk of human papillomavirus infection and disease after 5 years compared withy placebo ( high-quality evidence ).

Benefits

We found one RCT (published in 2 papers). The RCT compared quadrivalent vaccine (HPV-6, 11, 16, and 18) versus placebo in young women (mean age 20 years). The RCT found significantly less infection associated with HPV-6, 11, 16, and 18 at 5 years with vaccine compared with placebo (4/256 [2%] with vaccine v 58/254 [23%] with placebo; efficacy 93.5%, 95% CI 82.5% to 98.3%). The RCT also found that there was significantly less disease associated with HPV-6, 11, 16, and 18 at 5 years with vaccine compared with placebo (0/266 [0%] with placebo v 10/263 [4%] with placebo; efficacy 100.0%, 95% CI 55.3% to 100.0%).

Harms

The RCT reported no serious adverse effects related to the vaccine. It found a similar number of vaccine-associated adverse effects between the vaccine and placebo (243/272 [89%] with vaccine v 225/274 [82%] with placebo; significance assessment not performed).

Comment

Clinical guide:

The HPV vaccine is an important medical development. In the United States it is licensed for females aged 9 to 26, based on the ages of the study population; males are being studied. Elsewhere (e.g. Australia and New Zealand) it has been approved for both sexes. The quadrivalent vaccine has been given to over 40,000 people in study protocols, and subsequently to many more. With the study population and subsequent use by over 1,000,000 people, the safety profile is favourable, with no severe problems identified, and only principally injection site discomfort. It is recommended to avoid vaccination during pregnancy.

Substantive changes


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