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

Imiquimod

Imiquimod is an immunomodulator and acts by modifying the immune response, specifically the response of the innate immune system. 52 Binding of imiquimod to toll-like receptor 7 triggers the cellular release of cytokines. Studies report that treatment with imiquimod leads to increases in levels of the cytokines interferon-alpha, interleukin-1beta, interleukin-6 and tumour necrosis factor-alpha. 52–54 Cytokines act to boost the body’s defences by blocking multiplication of invading pathogens, including viruses.

Formulated as a 5% cream (12.5 mg of imiquimod in 250 mg of cream) for application by the patient, imiquimod is licensed by the European Medicines Agency (EMA)55 and the US Food and Drug Administration (FDA)56 for the topical treatment of:

• external genital and perianal warts (condylomata acuminata) in adults

• small superficial basal cell carcinomas in adults

• clinically typical, non-hyperkeratotic, non-hypertrophic actinic keratoses on the face or scalp in immunocompetent adult patients when size or number of lesions limits the efficacy and/or acceptability of cryotherapy and other topical treatment options are contraindicated or less appropriate.

In addition, imiquimod 3.75% cream is also licensed by the FDA for the treatment of external AGWs. 57

According to the Summary of Product Characteristics (SmPC), when treating AGWs, imiquimod 5% cream should be applied topically three times per week on non-consecutive days (e.g. Monday, Wednesday and Friday or Tuesday, Thursday and Saturday) before normal sleeping hours. 58 It is advised that the cream be applied in a thin layer to clean skin involving lesions and, after smoothing completely into the skin, the cream should be left in place for 6–10 hours. After this period, the treated area should be washed with mild soap and water. Application of an excess of cream or prolonged contact with the skin might result in a severe application site reaction.

In studies evaluating the clinical effectiveness of imiquimod, local skin reactions were often the most common AE, with people experiencing erythema (61%), erosion (30%), excoriation/flaking/scaling (23%) and oedema (14%). 58 It is important that people understand that a degree of inflammation is to be expected and represents the local immune response, which is beneficial in clearing the infection. People also reported systemic AEs, including headache, nausea and myalgia.

Imiquimod is contraindicated in people who are hypersensitive to imiquimod or to any of the excipients in the formulation. 58 As imiquimod elicits an effect through stimulating the immune system, caution is advised when using imiquimod in the treatment of people who are receiving immunosuppressive treatments.

The British National Formulary (BNF)39 lists the net price of a pack of 12 sachets of Aldara as £48.60.

Podophyllotoxin

Podophyllotoxin is the most abundant lignan extracted from the resin podophyllin, which is itself isolated from species of the Podophyllum family. 59 Podophyllotoxin inhibits the action of topoisomerase II, an enzyme involved in DNA replication. Blocking topoisomerase II activity prevents cellular division and therefore multiplication of AGW cells. As AGW cells die, they are replaced by non-HPV-infected cells.

Podophyllotoxin has been evaluated in RCTs at various doses in gel, solution and cream formulations. 60–68 No preparation of podophyllotoxin is licensed by the EMA or FDA for the treatment of AGWs, but UK marketing authorisations have been granted for podophyllotoxin 0.5% solution (Condyline^®, Takeda Pharmaceuticals Company Ltd; Warticon^® solution, Stiefel Laboratories Ltd) and 0.15% cream (Warticon^® cream, Stiefel Laboratories Ltd) preparations.

All podophyllotoxin preparations are for the treatment of external AGWs only. The SmPCs for the three podophyllotoxin-based treatments available in the UK indicate that, irrespective of formulation, the preparation should be applied directly to the AGWs twice daily for 3 consecutive days. 69–71 The SmPCs outline that, if required, the treatment schedule can be repeated at weekly intervals for a maximum of 4 weeks in the case of Warticon (cream and solution)70,71 and 5 weeks in the case of Condyline. 69 Because of the destructive effect of podophyllotoxin on cells, care should be taken to apply the preparation only to the affected area.

Preparations containing podophyllotoxin are contraindicated in people who:

• are hypersensitive to podophyllotoxin or to any of the other ingredients

• have open or bleeding lesions

• are using another podophyllin- or podophyllotoxin-containing preparation. 69–71

Additionally, Condyline is contraindicated in pregnant or breastfeeding women and children aged < 12 years. 69

As with imiquimod 5% cream, the most common AEs associated with podophyllotoxin preparations are reactions at the application site, including erythema, pruritus and a skin-burning sensation. Skin erosion is also common with podophyllotoxin-based applications. 69–71

The BNF39 lists a net price for Condyline of £14.49 for a 3.5-ml bottle with applicators compared with £14.86 for 3.0 ml (with applicators) of Warticon solution. Podophyllotoxin 0.15% cream is available at a net cost of £17.83 for 5 g, together with a mirror to aid application.

Cidofovir

Cidofovir is a monophosphate nucleotide analogue. 72 Conversion of cidofovir to the biphosphate form produces a metabolite that is a competitive inhibitor and an alternative substrate for viral DNA polymerases (DNA polymerase is an enzyme that is essential for DNA replication). Incorporation of the biphosphate form of cidofovir into the growing DNA chain in preference to the natural substrate of deoxycytidine triphosphate disrupts further elongation of the chain and thus viral replication. 72 As cidofovir acts directly on viral DNA, it has been proposed that topical cidofovir does not require a competent immune system to be effective and thus could potentially afford greater clinical benefit for people with HIV infection than with other treatments available. 73

At the time of writing, cidofovir is not licensed for the treatment of AGWs. Cidofovir is licensed by the EMA74 and FDA75 for intravenous use in the treatment of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome who do not have kidney disease (as cidofovir is associated with nephrotoxicity). As a potent inhibitor of viral DNA polymerase, there is considerable interest in the potential of cidofovir as a treatment for other conditions caused by viruses. Several in vivo and in vitro studies report the effectiveness of cidofovir against a range of DNA virus and retrovirus infections, including papillomavirus, adenovirus and herpes virus. 76 Additionally, small studies and case reports describe the effectiveness of topical and intralesional cidofovir in the treatment of virally induced skin conditions. 76 For the treatment of cutaneous disease, cidofovir has been formulated as a 1% gel and is applied topically to lesions overnight, three times a week for up to 16 weeks. 73

Podophyllin

Crude podophyllin is obtained as a powder. As noted earlier, the active metabolite in podophyllin is podophyllotoxin. The process to extract podophyllin from species of the Podophyllum family is not standardised and thus the concentration of podophyllotoxin can differ markedly from batch to batch of podophyllin. 59 Additionally, crude podophyllin has not been subject to rigorous investigation and the remaining constituents of the crude product have not been well characterised. Identification of the mutagenic flavenoids quercetin and kaempferol in crude podophyllin led to concern about the potential for exacerbation of oncogenic HPV-associated intraepithelial neoplasia77,78 (quercetin and kaempferol constitute 3% and 6% of the dry weight of podophyllin powder, respectively77,79,80). As a result of the concerns about toxicity and the varying concentration of podophyllotoxin, the use of podophyllin is no longer recommended. 6,7

For clinical use, crude podophyllin is added to a benzoin tincture to create a resin that is painted onto lesions. Podophyllin resin is not licensed by the EMA or FDA for the treatment of AGWs but has been approved by the Medicines and Healthcare products Regulatory Agency (the UK marketing authority) for the treatment of plantar warts and AGWs. 81 Because of the corrosive nature of the treatment, podophyllin must be applied by a clinician and care must be taken to avoid applying the resin to the surrounding skin; it is recommended that surrounding skin be covered with soft paraffin to protect against treatment. After application, the treated area should be covered with soft paraffin and left for a maximum of 6 hours, after which the podophyllin resin should be washed off. 81 Podophyllin is typically applied once weekly until complete clearance.

Podophyllin should not be used in women who are pregnant or breastfeeding and should not be used to treat facial warts. 81 Severe toxicity associated with absorption of podophyllin has been reported. Consequently, when a person presents with a large number of AGWs, it was recommended that only a few be treated at a time to reduce the risk of systemic toxicity. 81

Trichloroacetic acid

Trichloroacetic acid is a caustic agent used in various cosmetic treatments including facial peels and tattoo removal as well as for the treatment of AGWs. 82 Typically used at a concentration of 80–90% in the treatment of AGWs, TCAA destroys cellular proteins, which results in cell death. TCAA preparations are not licensed by the EMA or FDA for treatment of AGWs. Despite the lack of a licence, TCAA is recommended for the treatment of AGWs, particularly soft non-keratinised AGWs. 5 Incorrect application of TCAA can damage healthy skin and therefore it is not suitable for home application. If considered an appropriate treatment, TCAA is applied once weekly. Complete clearance of AGWs can occur after a single application, but most people will require multiple courses of treatment. The most common AEs of treatment are pain or burning during administration, with some people experiencing an intense burning sensation for 5–10 minutes after application. Ulceration after application of TCAA can also occur, which makes TCAA unsuitable for the treatment of AGWs of large volume. Despite the listed AEs, TCAA is thought to be the safest of the available topical treatments for use during pregnancy. 1

Population

Inclusion criteria varied considerably across identified studies, with some studies reporting clinical diagnosis of AGWs as the sole criterion for eligibility (see Table 4). The size of studies was also wide-ranging, with the largest study randomising 450 people151 and the smallest randomising 12 people. 120

Few identified studies reported comprehensive baseline characteristics for the enrolled study population. Key characteristics of AGWs that potentially influence treatment choice and effectiveness include size, number and location of lesions, together with wart type (keratinised vs. non-keratinised). Of those studies reporting baseline characteristics, most studies included a mixed population in terms of AGW characteristics. AGW morphology was rarely specified as an inclusion criterion and only one study61 was identified that restricted inclusion by AGW type, specifying that AGWs should be non-keratinised. Most studies evaluated the treatment of external AGWs. One study155 was identified that evaluated treatment of intra-anal AGWs. Duration of AGWs and line of treatment also varied across studies. Some studies focused on people who were treatment naive or restricted inclusion to those who had not received treatment in a set time period before enrolment, typically the preceding 3 months. As well as varying across studies, duration of disease varied considerably within studies, for example ranging from 1 to 300 weeks in the study by Godley et al. 154

Several studies specified a minimum age for eligibility of 18 years and the reported mean age of people enrolled in studies ranged from 20 to 35 years. Although many studies included both genders, 1861,66,67,115,123,127,129,133,136,140,142,143,145,147,150,154,160,162 and eight62,122,124,126,130,134,137,161 studies focused on men and women respectively. Three studies evaluated treatments in people with HIV infection. 119,120,128

The generally limited reporting of baseline characteristics precludes discussion of the extent of clinical heterogeneity across studies. Given the limited information available, clinical experts were consulted about the potential disparity across studies in populations enrolled. Experts fed back that they considered the population across the studies likely to be representative of people with AGWs and who present to GUM clinics. Thus, the project team considered it appropriate to carry out a MTC.

Interventions and comparators

Studies evaluating all interventions of interest were identified (see Table 4). Topical treatments evaluated were the self-applied imiquimod 5% cream and podophyllotoxin, and the clinician-applied TCAA and podophyllin 20–25%. Various concentrations (e.g. podophyllotoxin 0.5% cream and 0.15% cream), formulations (e.g. podophyllotoxin 0.5% cream and podophyllotoxin 0.5% solution) and application schedules of podophyllotoxin were evaluated across studies. Additionally, the duration of treatment with imiquimod 5% cream varied across studies. The licence for imiquimod 5% cream indicates that treatment can be given for up to 16 weeks and recommends an application schedule of three times per week on non-consecutive days. 58 Studies were identified evaluating application of imiquimod 5% for 4, 8, 12 and 16 weeks130,133 and at application schedules of once daily, twice daily and three times daily. 129,134

After consultation with clinical experts on the potential influence of treatment duration, dose and formulation (relates to ease of application) on clinical effectiveness, the following assumptions were made for the purposes of carrying out meta-analysis, both direct and indirect:

• Imiquimod 5% cream of any schedule (e.g. three times a week vs. once daily vs. twice daily) applied for 12 weeks is equivalent in clinical effectiveness to imiquimod 5% cream applied for 16 weeks; schedules of < 12 weeks’ duration were excluded from the analysis.

• Clinician-applied podophyllin 20% and clinician-applied podophyllin 25% are clinically equivalent.

• Different formulations of podophyllotoxin are of potentially sufficiently dissimilar clinical effectiveness to warrant analysis by preparation.

• With the exception of podophyllotoxin 0.25% and 0.3%, doses of podophyllotoxin are potentially of sufficiently dissimilar clinical effectiveness to warrant analysis by dose.

Outcomes

The outcomes of interest to this review and reported in the included studies are listed in Table 5. No study reported data on the outcomes of relief of symptoms, malignancy or QoL. Although most studies presented results on the primary outcome of complete clearance of AGWs at the end of treatment, few studies presented data on complete clearance at subsequent time points. The definition of recurrence of AGWs differed slightly across studies. Most studies defined recurrence as the appearance of AGWs at a site previously cleared of AGWs, whereas some included appearance of AGWs at sites additional to those initially cleared.

Quality assessment

No study was deemed to be at an overall low risk of bias, with the largest proportion of studies categorised as having an overall unclear risk of bias predominantly because of the limited reporting in the full publications (Table 6). In an attempt to supplement the information available, study authors were contacted with requests for additional detail on trial methodology. Only two authors replied by the prespecified deadline. Given that it is over 10 years since publication of most of the identified studies, the low response rate was to be expected.

All studies were described as randomised but details on methods used to generate the randomisation sequence were rarely reported. Assessment of clearance and recurrence of AGWs was subjective and thus at risk of bias. Most studies involving topical applications were described as double blinded but, as for randomisation, the full publications provided little information on methods implemented to initially conceal allocation and to subsequently maintain masking of treatment from clinicians and participants. Additionally, for most studies described as double blind, it was unclear whether or not the outcome assessor was the treating clinician and, if not, if the outcome assessor was masked to treatment. Some studies evaluating topical treatments were described as open label in design and thus were categorised as being at high risk of bias for most outcomes reported (see Table 6). Differences in setting could make implementation of masking problematic in studies evaluating self-applied against clinician-applied treatments and topical against ablative therapies. However, masking in these studies could be achieved using sham treatments.

Follow-up at the end of treatment was generally high across studies, with several studies categorised as being at low risk of attrition bias for the outcomes evaluated. However, follow-up at later time points to evaluate recurrence was variable, with high rates of loss to follow-up reported in several studies. Authors of some studies suggested that the low rate of return for further assessments could be attributed to treatment success, that is, complete clearance of AGWs without recurrence had been achieved and people felt that they needed no additional treatment or monitoring.

Of the domains relating to study characteristics, selective reporting was the domain most frequently determined to be at a high risk of bias (see Table 6). In these cases, results for the primary clinical effectiveness outcomes for this project (complete clearance and recurrence) were either not reported, despite being listed in the publication as a primary outcome, or not reported in a way that facilitated incorporation of the data into meta-analysis.

Recurrence at < 6 months

Applying the clinical assumptions outlined earlier identified four studies127,140,145,148 to inform the primary analysis of recurrence occurring at < 6 months, which facilitated indirect comparison of:

• podophyllin 20–25%

• podophyllotoxin 0.5% solution

• podophyllotoxin 0.25% solution

• TCAA

• TCAA plus podophyllin 20–25%.

The random- and fixed-effects models were similar in terms of goodness of fit (DIC 44.4 vs. 44.4, respectively) and had the same residual deviance (8.3 vs. 8.3, respectively), which was close to the number of unconstrained data points in the analysis (eight data points). However, because of the possibility of clinical heterogeneity in the populations of the trials combined in the network, the random-effects model was preferred.

There were no statistically significant differences between any comparisons for recurrence at < 6 months; results from the MTC are presented in Appendix 9. TCAA was associated with the lowest probability of recurrence (23.4%, 95% CrI 1.5% to 76.6%). By contrast, podophyllotoxin 0.25% solution had the highest probability of recurrence (66.9%, 95% CrI 5.2% to 99.5%). The probability of recurrence for all treatments is presented in Figure 11.

FIGURE 11.

Probability of recurrence at < 6 months by treatment: primary analysis.

Sensitivity analysis of recurrence at < 6 months included an additional six studies64,67,136,137,142,151 and six other interventions:

• podophyllotoxin 0.5% cream

• podophyllotoxin 0.3% cream

• podophyllotoxin 0.15% cream

• podophyllin 0.5% solution (patient applied)

• cryotherapy

• electrotherapy.

The probability of recurrence for all treatments included in the sensitivity analysis is presented in Figure 12. Of the 11 interventions analysed, TCAA had the lowest probability of recurrence (24.7%, 95% CrI 8.7% to 46.9%). In marked contrast, podophyllotoxin 0.25% solution (83.3%, 95% CrI 49.5% to 98.5%) and podophyllin 0.5% solution (75.9%, 95% CrI 22.0% to 99.5%) had the highest probabilities of recurrence. The comparatively high probability of recurrence of the two topical treatments is reflected in the results of the MTC. As in the primary analysis, for most comparisons, the differences between interventions did not reach statistical significance. However, six comparisons were statistically significant, with four of these involving podophyllotoxin 0.3% solution and with the direction of effect favouring the comparator (podophyllotoxin 0.5% solution, TCAA, cryotherapy and electrotherapy). Additionally, TCAA was significantly more effective than podophyllin 20–25% (OR 0.35, 95% CrI 0.09 to 0.88) and podophyllotoxin 0.15% cream (OR 0.30, 95% CrI 0.06 to 0.90) at reducing recurrence at < 6 months. Full results of the MTC are presented in Appendix 9.

FIGURE 12.

Probability of recurrence at < 6 months by treatment: sensitivity analysis.

Recurrence at ≥ 6 months

Four studies132,138,146,155 reported recurrence at ≥ 6 months and informed the primary MTC, three132,138,146 of which were included in the MTC. No additional studies were identified for inclusion in a sensitivity analysis.

The random- and fixed-effects models had a similar goodness of fit (32.8 vs. 32.8, respectively). However, the fixed-effects model had a slightly lower residual deviance than the random-effects model (6.1 vs. 6.2, respectively), which is close to the number of unconstrained data points in the analysis (six data points).

The network generated evaluated four interventions:

• podophyllin 20–25%

• imiquimod 5% cream

• podophyllotoxin 0.5% solution

• surgical excision.

Of the comparisons evaluated, only two differences were statistically significant. Surgical excision was found to be statistically significantly more effective than podophyllin 20–25% (OR 0.16, 95% CrI 0.03 to 0.43) and podophyllotoxin 0.5% solution (OR 0.14, 95% CrI 0.02 to 0.50) at reducing recurrence at ≥ 6 months. Full results of the MTC are presented in Appendix 9. Surgical excision was also associated with the lowest probability of recurrence of the four treatments (15.4%, 95% CrI 4.7% to 33.5%; summarised in Table 12).

An additional study not included in the MTC155 investigated whether or not argon plasma coagulation in combination with imiquimod 5% cream was more effective than argon plasma coagulation alone in the treatment of intra-anal AGWs. Viazis et al. 155 found no statistically significant difference between the two treatments for recurrence of AGWs at a mean follow up of 6 months [5/22 people recurred with combination treatment vs. 8/23 people recurred with monotherapy; OR 0.55 (calculated by project authors), 95% CI 0.15 to 2.06].

Clearance of anogenital warts of < 50%

Arican et al. 112 and Snoeck et al. 121 compared imiquimod 5% cream and cidofovir 1% gel, respectively, with placebo. The third study132 compared imiquimod 5% cream with podophyllin 20–25%.

The fixed-effects model was a slightly better fit than the random-effects model (DIC 28.6 vs. 28.7, respectively). The residual deviance of the fixed-effects model was also similar to the number of unconstrained data points analysed (residual deviance of 6.4 compared with six data points, respectively).

The MTC using the fixed-effects model indicated that the effect estimate for achieving < 50% clearance of AGWs was statistically significantly lower with imiquimod 5% cream than with placebo and cidofovir 1.0% gel (Table 13). For the comparison of imiquimod 5% cream and podophyllin 20–25%, the estimate of effect approached 1 and the difference between the treatments did not reach statistical significance.

Clearance of anogenital warts of ≥ 50%

Five interventions were evaluated in the MTC:

1. placebo or no treatment

2. imiquimod 5% cream

3. podophyllotoxin 0.5% solution

4. podophyllin 20–25%

5. cidofovir 1% gel.

The fixed-effects model was a better fit than the random-effects model (DIC 64.2 vs. 65.3, respectively). The residual deviance of the fixed-effects model was also similar to the number of unconstrained data points in the analysis (11.7 vs. 12, respectively).

Based on the fixed-effects model, podophyllotoxin 0.5% solution was found to be significantly more effective than imiquimod 5% cream and placebo at reducing the volume of AGWs by ≥ 50% compared with the baseline volume (Table 14). No other difference between treatments achieved statistical significance.

Ulceration

Abdullah et al. 153 and Godley et al. 154 compared TCAA with cryotherapy and reported on the occurrence of ulceration. In both studies, a larger proportion of people in the TCAA group than in the cryotherapy group experienced ulceration. Standard pairwise meta-analysis using the fixed-effects model found that TCAA was associated with a significantly higher risk of ulceration than cryotherapy (OR 0.22, 95% CI 0.10 to 0.46; p < 0.0001); the forest plot is presented in Figure 13. However, the level of heterogeneity in the analysis was high (I² = 68%). Using a random-effects model as a sensitivity analysis generated a non-statistically significant difference between treatments (OR 0.13, 95% CI 0.01 to 1.62; p = 0.11).

FIGURE 13.

Forest plot for the comparison between cryotherapy and TCAA for the outcome of ulceration. df, degrees of freedom; M–H, Mantel–Haenszel.

Blistering

In a comparison of cryotherapy and CO₂ laser therapy, Azizjalali et al. 156 found a low occurrence of blistering in each treatment group, with two and no people in the cryotherapy and CO₂ laser therapy groups, respectively, experiencing blistering (80 people were randomised to each group).

Erythema

Seven RCTs informed the MTC of erythema,60,61,112,116,118,123,132 generating a network incorporating five interventions:

1. placebo or no treatment

2. imiquimod 5% cream

3. podophyllin 20–25%

4. podophyllotoxin 0.5% solution

5. podophyllotoxin 0.5% cream.

The fixed-effects model was found to be a better fit than the random-effects model (DIC 75.0 vs. 76.2, respectively), with a similar residual deviance to the number of unconstrained data points (14.8 vs. 15, respectively).

Using the fixed-effects model with imiquimod 5% cream as baseline, the MTC found that all active interventions were associated with a statistically significant increase in risk of erythema compared with placebo (Table 16). However, no statistically significant differences in erythema were identified across the comparisons of active interventions (see Table 16).

Of the five interventions compared, podophyllotoxin 0.5% solution was associated with the highest probability of occurrence of erythema:

1. placebo or no treatment: 19.1% (CrI 13.1% to 26.3%)

2. imiquimod 5% cream: 60.3% (95% CrI 52.6% to 67.7%)

3. podophyllin 20–25%: 44.5% (95% CrI 24.3% to 66.1%)

4. podophyllotoxin 0.5% solution: 66.8% (95% CrI 31.8% to 92.0%)

5. podophyllotoxin 0.5% cream: 50.9% (95% CrI 21.2% to 81.7%).

Oedema

The studies by Beutner et al. ,116 Edwards et al. 118 and Padhiar et al. 132 were included in the MTC of oedema, facilitating comparison of imiquimod 5% cream, podophyllin 20–25% and placebo or no treatment.

The best-fitting model was the fixed-effects model, with a DIC of 31.5 compared with 32.3 for the random-effects model. Additionally, the fixed-effects model was a good fit for the data (residual deviance of 5.1 compared with six unconstrained data points in the analysis).

Imiquimod 5% cream and podophyllin 20–25% both statistically significantly increased the risk of oedema compared with placebo:

• imiquimod 5% cream: OR 0.05 (95% CrI 0.01 to 0.13; OR < 1 favours placebo)

• podophyllin 20–25%: OR 316.2 (95% CrI 39.86 to 1304; OR > 1 favours placebo).

Additionally, podophyllin 20–25% was found to statistically significantly increase the risk of oedema compared with imiquimod 5% cream (OR 12.39, 95% CrI 2.74 to 40.21; OR > 1 favours imiquimod 5% cream).

Itching

Three studies informed the MTC of itching,61,116,132 enabling comparison of imiquimod 5% cream, podophyllin 20–25%, podophyllotoxin 0.5% solution and placebo or no treatment.

The random- and fixed-effects models were similar in terms of goodness of fit (DIC 35.2 vs. 35.2, respectively) and had the same residual deviance (6.1 vs. 6.1, respectively), which was close to the number of unconstrained data points in the analysis (six data points). However, because of the possibility of clinical heterogeneity in the populations of the trials combined in the network, the random-effects model was preferred.

There was no significant difference in the risk of itching between any of the active treatments compared with placebo (Table 17). Similarly, there was no significant difference between any of the active treatments compared with one another for this adverse event.

Of the active interventions, podophyllin 20–25% had the highest probability of being associated with itching (51.2%, 95% CrI 6.8% to 93.7%). Imiquimod 5% cream and podophyllotoxin 0.5% solution had similar probabilities of being associated with itching, at 30.7% (95% CrI 21.5% to 40.6%) and 39.9% (95% CrI 0.1% to 96.5%), respectively.

Duration of treatment

The duration of treatment for trials included in the MTC varied (see Chapter 3, Quantity and quality of research available). Thus, the average duration of treatment seen in UK clinical practice was modelled based on consultation with clinical experts, ensuring comparability with the range of treatment durations investigated in the included clinical trials. The duration of treatment modelled in the base case for each intervention is presented in Table 22, alongside the duration of treatment analysed in the included clinical trials.

It was therefore assumed that the treatment effect estimated from the MTC based on the included clinical trials was independent of treatment duration (see Chapter 3, Assessment of effectiveness). In addition, as CO₂ laser therapy and surgery are typically carried out in one session, the average duration of treatment modelled is intended to reflect the typical waiting time for the procedure.

Because of the variability in treatment duration, the impact of uncertainty in these parameters was tested in a sensitivity analysis.

Duration of follow-up

Duration of follow-up was assumed to be 12 weeks for all interventions. This was based on clinical expert opinion and was selected to capture any recurrence of AGWs that would be considered part of the original episode of AGWs in clinical practice. This duration was tested in sensitivity analysis.

Treatment sequences

Within the base-case analysis, people with AGWs were assumed to receive up to two lines of treatment for their AGWs before being classed as having persistent AGWs. Complete clearance data at the end of the treatment were available for 11 interventions (see Complete clearance at the end of the treatment); thus, the total number of possible treatment sequences equalled 121. However, on the basis of the following assumptions, 84 possible treatment sequences were modelled (Table 23):

• ‘No treatment’ will be prescribed first line only, that is, an active intervention will always be prescribed second line.

• No sequence of treatments will involve the same intervention twice, that is, if a patient fails on one intervention they will not be prescribed that intervention again. This is assumed to include combinations of therapy, for example a patient prescribed podophyllin first line would not receive cryotherapy in combination with podophyllin second line.

These assumptions were verified through consultation with clinical experts.

Data were not identified for all interventions included within the analysis

The following interventions for which data were identified for the outcome of complete clearance had no data identified for the outcome of recurrence: no treatment, podophyllotoxin cream (sensitivity analysis only), CO₂ laser therapy, cryotherapy, cryotherapy plus podophyllin 25% and cryotherapy plus podophyllotoxin 0.15% cream.

To include recurrence data within the base-case model for these interventions, clinical expert opinion was sought. The resulting probabilities of recurrence used within the base-case economic analysis are presented in Table 29.

Data analysed included follow-up periods of 3–12 months, in contrast to the required data for the model including follow-up for up to 3 months

The data identified from the systematic review of the clinical literature for recurrence of AGWs were limited; thus, to provide a connected network from which data on recurrence could be estimated for use within the economic analysis, data from the assessment of recurrence at 3–12 months were combined in a MTC (see Appendix 8).

The baseline treatment effect was estimated using only data from 3 months. However, for the relative effects, it is necessary to assume that the relative difference in probability of recurrence between interventions will not differ over time. This is acknowledged as a weakness of the analysis and an area where further research is considered important.

To test the importance of recurrence data within the model, a number of sensitivity analyses were carried out:

• setting the same probability of recurrence for all interventions:

  • setting the probability of recurrence to the average rate estimated from the MTC

  • setting the probability of recurrence to 0%

  • setting the probability of recurrence to 100%.

The results of these analyses are described in Sensitivity analysis.

Systematic review of existing health-related quality-of-life data

A systematic review was carried out in September 2013 to identify relevant published HRQoL evidence to populate the economic model. The following databases were searched from inception:

• MEDLINE (Ovid MEDLINE In-Process & Other Non-Indexed Citations and Ovid MEDLINE)

• EMBASE (Ovid EMBASE)

• CENTRAL (The Cochrane Library)

• HTA database (The Cochrane Library)

• NHS EED (The Cochrane Library).

The search strategy for all databases combined terms to capture AGWs and HRQoL. Full details of the search terms are presented in Appendix 1. In addition to searching the above databases, reference lists of identified studies were reviewed for any potentially relevant studies. No restrictions on language or setting were applied to any of the searches. Studies were assessed for inclusion based on the criteria outlined in Table 30.

The systematic review was updated in March 2014. The search strategy remained the same as outlined above; however, results were limited from 2013 to March 2014 to identify only additional relevant studies.

In total, 468 studies were identified from the September 2013 database search (Figure 19). Two health economists reviewed all citations. Of these, 148 were identified as duplicates and 201 studies were excluded on the basis of title and abstract. A total of 119 papers were therefore identified as potentially relevant. Of these papers, 12 were identified from the abstract as either reporting condition-specific measures of HRQoL or generic non-preference-based measures of HRQoL, and 107 papers were identified as reporting possible generic, preference-based measures of HRQoL (Q1, see Table 30). If it was unclear which type of HRQoL measure was included in the study, the reviewer was inclusive and labelled the study as including a potential generic, preference-based measure of HRQoL.

FIGURE 19.

Identified HRQoL studies, September 2013 search.

The 12 studies identified as reporting either condition-specific measures of HRQoL or generic, non-preference-based measures of HRQoL were provisionally included, that is, these studies were not ordered in full in the first instance. However, as suitable studies reporting the use of generic, preference-based measures of HRQoL were identified, the 12 studies reporting either condition-specific measures of HRQoL or generic, non-preference-based measures of HRQoL were not included in the review. This is because a generic, preference-based measure of HRQoL, such as the European Quality of Life-5 Dimensions (EQ-5D), was considered preferable for use within an economic evaluation, based on the NICE Guide to the Methods of Technology Appraisal. 221 It was therefore considered appropriate to assess the suitability of condition-specific or generic non-preference-based measures of HRQoL, if, and only if, no suitable generic, preference-based measures of HRQoL were identified.

Following review of the 107 studies potentially reporting generic, preference-based measures of HRQoL, 10 studies were included in the review; seven studies32,176,222–226 were identified as reporting generic non-preference-based measures of QoL and three studies227–229 were identified as reporting condition-specific measures of QoL. In addition to the studies identified through the database search, three studies230–232 were identified through review of reference lists as reporting generic, preference-based measures of HRQoL.

A total of 88 studies were excluded. Of these, two were not retrievable; two were duplicate references; 57 did not contain any QoL data; and 27 were excluded on the basis that the study reported a measure of QoL from another study. The most commonly cited reference was a conference abstract by Myers et al. 233 The figures within the study were described as being elicited using time trade-off methods and therefore may constitute a generic, non-preference-based measure of HRQoL. The abstract was presented at the 21st International Papillomavirus Conference in Mexico in 2004. Unfortunately, it was not possible to retrieve the full paper for this reference as the study appears to be unpublished. Consequently, it was not possible to verify these QoL values.

A further 49 papers were identified from the updated search in March 2014. Of these, four papers were identified as potentially relevant and ordered for full review, of which three234–236 were excluded on the basis of the full paper and one237 was identified as including generic, preference-based HRQoL data.

A total of 14 studies from the September 2013 (13 studies32,176,222–232) and March 2014 (one study237) searches therefore reported relevant generic, preference-based HRQoL data. Information on the populations, health states, instruments and utility values reported in these studies is presented in Appendix 2; a summary of the HRQoL instrument used in each included study is presented in Table 31.

Data from the UK were considered to be most relevant for this review in the first instance. Of the 14 identified studies, six contained HRQoL data for people from the UK. 32,176,228,230,231,237 These studies are described in further detail below.

Dominiak-Felden et al. 237 reported data from a large, multicentre, observational study carried out in the UK to investigate the impact of HPV-related genital diseases on QoL and psychosocial well-being. A total of 2502 individuals aged 18–64 years from 15 UK centres were screened for inclusion into the study between May 2008 and March 2009. Of those screened, 1512 people met the screening criteria and 1272 were included in the study after confirmation of diagnosis.

A subset of 186 people was found to have a current episode of genital warts. These participants were, on average, aged 28 years and 46% were female. It was not reported what proportion of patients were experiencing their first episode compared with a recurrent episode. People with a current episode of genital warts were invited to complete the EQ-5D questionnaire; the results are presented in Table 32.

The authors found that there was no significant difference in the overall EQ-5D score between people with genital warts and the general population when scores were weighted to match the age and sex profile of the general population. However, the authors found that people with genital warts reported, on average, statistically significantly greater issues with anxiety and depression than the age- and sex-matched general population (p < 0.001) and fewer issues with the remaining dimensions of the EQ-5D: mobility (p = 0.007), self-care (p = 0.083), usual activities (p = 0.005), pain and discomfort (p = 0.158).

The authors considered age subgroups (18–24 years and 25–34 years) and found statistically significant differences in HRQoL compared with the age- and sex-matched general population (see Table 32); no sample sizes were stated for these analyses.

Woodhall et al. 176 reported a study carried out in seven sexual health clinics in England (six clinics) and Northern Ireland (one clinic). Between August 2009 and February 2010, a total of 895 people aged ≥ 16 years with a current diagnosis of genital warts were invited to complete an EQ-5D questionnaire. The average age of respondents was 28 years (range 16–73 years) and 65% of people were attending for their first episode. EQ-5D scores from people with genital warts were compared with age- and sex-matched average scores from the UK population. The authors noted that HRQoL associated with genital warts differed between women and men; therefore, a utility score for a health state including genital warts was presented by gender, as was an estimate of disutility associated with genital warts (Table 33).

Furthermore, Woodhall et al. 176 noted that no significant difference in HRQoL was observed between the first and recurrent episodes of AGWs; however, disutility was found to differ between age groups and this difference was statistically significant (p < 0.0001). The highest loss of QoL was seen in women aged 16–19 years and men aged 35–44 years. The numbers of patients in each of the different age groups were not presented.

Within the study, a further two UK studies reporting EQ-5D scores for people with AGWs were referenced. Both studies were conference abstracts published as part of the Eurogin 2010 Conference. 230,231 Neither study was identified in the original search; however, these studies were extracted in full and are presented in Appendix 2.

Fiander and Cohet230,231 present data relating to an observational, cross-sectional study in which 1264 subjects (women and men) aged 18–64 years with HPV-related diseases were recruited from 15 community and hospital health-care clinics; the first abstract reports results relating to women230 and the second reports results relating to men. 231 The study is related to the full paper by Dominiak-Felden et al. ,237 described above. The abstacts present EQ-5D data for a subset of the full study population, specifically, women and men aged 18–25 years with genital warts. The sample size for each analysis is not reported. The EQ-5D score for genital warts was estimated to be 0.83 and 0.89 for women and men aged 18–25 years, respectively. No estimates of uncertainty were presented.

Langley et al. 228 presented a conference abstract in which results from an internet-based survey carried out in the UK, France, Spain, Italy and Germany were published. A reported 53,524 people responded to the survey, with 521 reporting external genital warts. Respondents completed the Short Form questionnaire-6 Dimensions (SF-6D), from which the authors carried out a regression analysis controlling for presence or absence of genital warts, sociodemographic characteristics, health risk factors and the Charlson Comorbidity Index (an index that predicts the 10-year mortality rate for a person who may have a range of comorbid conditions). The disutility associated with external genital warts using the SF-6D (utilities scaled as 0–100) was consequently estimated as –2.47 (95% CI –3.58 to –1.36).

Woodhall et al. 32 reported a study of 81 adults attending the York GUM clinic with new, recurrent or persistent genital warts. Participants were invited to complete the EQ-5D questionnaire. EQ-5D scores from participants were compared with those in a control group of 1977 people in the same age range. Unadjusted EQ-5D scores were presented for people with and without genital warts. The authors estimated the mean EQ-5D score with genital warts (n = 81) to be 0.90 and the mean EQ-5D score without genital warts (n = 1977) to be 0.91. Adjusting for age and gender, the authors estimated a mean difference in EQ-5D score of 0.039 (95% CI 0.005 to 0.078) between people with and people without genital warts.

Health-related quality-of-life data selected for the economic analysis

Data from Woodhall et al. 176 were selected as the most relevant HRQoL data for the economic analysis. The baseline characteristics of the population presented in the study by Woodhall et al. 176 were considered to be reflective of the characteristics of the population seen in clinical practice in England and Wales. Moreover, the data presented in this study had a UK focus (England and Northern Ireland) and the study provided the largest reported sample of patients (895 vs. 186,237 8132 and 521228). In addition, the data were based on the most recent sample; although the data presented by Dominiak-Felden et al. 237 were published in 2013 (vs. 2011 for the study by Woodhall et al. 176), the questionnaires were completed in 2009–10 in the study by Woodhall et al. 176 and in 2008–9 in the study by Dominiak-Felden et al. 237

The population in Woodhall et al. 176 is described as people with ‘genital warts’. Although this differs from the focus for this analysis (i.e. both genital warts and AGWs), clinical experts advised that the terms ‘genital warts’ and ‘anogenital warts’ are often used interchangeably and the term ‘genital warts’ is considered appropriate to capture both genital warts and AGWs. It is therefore considered that the population is likely to include those with both genital warts and AGWs.

For the economic analysis, a mean estimate of HRQoL with and without AGWs was required; the estimates used within the economic analysis are presented in Table 34.

In the sensitivity analysis, to test the impact of using alternative HRQoL data, a scenario focusing on young adults was carried out. Based on findings from Woodhall et al. 176 and Dominiak-Felden et al. ,237 HRQoL in young adults appears to be more greatly impacted by AGWs than HRQoL in other age groups. Data for this scenario were taken from the study by Dominiak-Felden237 for those aged 18–24 years (HRQoL 0.86 with AGWs vs. 0.94 without AGWs).

No treatment

It is assumed that there is no acquisition cost associated with no treatment.

Patient-applied topical interventions

It is assumed that imiquimod 5% cream, podophyllotoxin 0.5% solution and podophyllotoxin 0.15% cream are applied by patients at home. The cost calculations for these treatments are presented in Table 36.

It was assumed that one item for podophyllotoxin 0.5% solution and podophyllotoxin 0.15% cream would be sufficient for the full treatment period. For imiquimod, it was assumed that four items were required per treatment period. It is acknowledged that, in clinical practice, some patients may be prescribed fewer imiquimod items on the basis that a patient may use fewer sachets per week; however, in the base case, the full treatment regimen was modelled. These assumptions were verified with clinicians and varied in a one-way sensitivity analysis to test their impact on the model results.

Provider-applied topical interventions

Podophyllin and TCAA were assumed to be applied by a clinician at a clinic. The cost calculations for these treatments are presented in Table 37.

No published list price for podophyllin or TCAA was identified. Thus, the costs for these interventions were estimated using data extracted from the systematic review of the cost and cost-effectiveness literature (see earlier in this chapter).

A cost for podophyllin was reported in two UK cost-effectiveness studies64,171 and two UK costing studies. 172,176 The most recent study reporting a price for podophyllin was that by Woodhall et al. 176 In this study, a cost of £0.02 was estimated for each use of podophyllin. In the model, it was assumed that five sessions would typically be required to apply a course of treatment. This was based on consultation with a clinical expert, who estimated that a typical patient would receive between four and six sessions to apply a course of treatment with podophyllin. This was tested in sensitivity analysis. The cost estimated within the study by Woodhall et al. 176 was inflated to current prices using the Hospital and Community Health Services (HCHS) inflation index from the Unit Costs of Health and Social Care 2013217 and was varied in sensitivity analysis.

A cost for TCAA was reported in one UK cost-effectiveness study171 and one UK costing study. 176 The most recent study reporting a price for TCAA was again that by Woodhall et al. 176 In this study, a cost of £0.32 was estimated for each use of TCAA. In the model, it was assumed that four sessions would typically be required to apply a course of treatment. This was on the basis of consultation with a clinical expert, who estimated that a typical patient would receive between three and five sessions to apply a course of treatment with TCAA. As with podophyllin, the cost estimated within the study by Woodhall et al. 176 was inflated to current prices using the HCHS inflation index217 and was varied in sensitivity analysis.

Provider-applied ablative interventions

Cryotherapy, CO₂ laser therapy and surgery were assumed to be carried out by a provider at a clinic. The cost calculations for these treatments are presented in Table 38.

The costs applied for these interventions were estimated using data extracted from the systematic review of the cost and cost-effectiveness literature.

A cost for cryotherapy was reported in one UK cost-effectiveness study171 and two UK costing studies. 175,176 The most recent study reporting a price for cryotherapy was that by Woodhall et al. 176 In this study, a cost of £4.27 was estimated for each use of cryotherapy. In the model, it was assumed that four sessions would typically be required to apply a course of treatment. This was on the basis of consultation with a clinical expert, who estimated that a typical patient would receive between three and five sessions of cryotherapy. As before, the cost estimated within the study by Woodhall et al. 176 was inflated to current prices using the HCHS inflation index217 and was varied in sensitivity analysis.

A cost for CO₂ laser therapy was reported in one UK costing study. 176 In this study, a cost of £125.49 was estimated per use. In the model, it was assumed that one treatment would typically be required per treatment period. This was on the basis of consultation with a clinical expert, who estimated that a typical patient would receive one treatment with CO₂ laser therapy. As before, the cost was inflated to current prices using the HCHS inflation index217 and was varied in sensitivity analysis.

For this analysis, the cost of surgical excision was taken from NHS reference cost values for 2012/13. 238 Specifically, the average cost associated with the outpatient procedure codes MA22Z and MA23Z (‘Minor Lower Genital Tract procedures’), weighted by activity, was applied within the model (£156). In the model, it was assumed that one session would typically be required per treatment period. This was on the basis of consultation with a clinical expert. It was assumed that the cost of an appointment in a GUM clinic would also be required. Reference costs were selected in place of national tariff data because reference cost figures are based on the actual reported estimated costs of coded procedures, whereas national tariff data represent the payments received by providers from the Department of Health for the coded procedures.

Combination therapies

The costs applied for combination treatments were estimated as the sum of the costs of each individual element, as shown in Tables 36–38. A summary of the applied costs is provided in Table 39.

Persistent warts

The one-off intervention cost associated with persistent warts applied in the model was £121.89. The description of how this figure was estimated is provided below.

Following review of the cost papers identified from the economic literature review, it was noted that Lanitis51 reported data relating to the number of additional appointments required for people with persistent warts. Within the study, a total of four consultants were interviewed. These consultants estimated that people with persistent warts typically required two additional appointments with a clinician compared with those without persistent warts.

Within the model, it was assumed that a further two visits would result in an average of two further lines of prescribed therapy. This is a simplifying assumption based on lack of data, as it is acknowledged that some people with persistent warts may be prescribed more or fewer lines of therapy. Additionally, the therapies prescribed for persistent warts were assumed to consist of either combination treatments or ablative therapies. This was based on the review of cost studies identified in the literature review and on consultation with clinical experts. Two of the identified cost studies presented the results of physician interviews around the likely treatments prescribed for persistent warts. 51,172

In the study by Lanitis,51 four consultants were interviewed. These consultants estimated that, for keratinised persistent warts, approximately 37.5% of people would be treated with ablative or combination therapy, with the remainder receiving topical monotherapy. For non-keratinised warts, approximately 25% of people were expected to be treated with ablative or combination therapy, with the remainder receiving topical monotherapy.

In the study by Brown et al. ,172 six GUM physicians were interviewed. The expected treatment for people with persistent warts was estimated by the physicians to be:

• cryotherapy (23%)

• diathermy procedure (23%)

• combination of a procedure and topical cream (22%)

• surgery (6%)

• topical cream (27%), of which imiquimod (98%) and podophyllotoxin (2%).

In addition, the clinical experts consulted for this project suggested that, in UK clinical practice, a patient with persistent warts would generally be treated with ablative therapy, most likely CO₂ laser therapy.

To take into account the variation in reported treatment for people with persistent warts, an average cost associated with combination therapies (cryotherapy plus podophyllin 25%, cryotherapy plus podophyllotoxin 0.15% cream, TCAA plus podophyllin 25%) and ablative therapies (cryotherapy, CO₂ laser therapy, surgical excision; for costs see Table 35) was used (£60.95) per additional appointment (two in the base case: £121.89). This figure was varied in sensitivity analysis.

Resource use

The resources modelled within the analysis specifically relate to appointments at GUM clinics. Table 40 provides a summary of the number of appointments applied within the economic analysis in the base case.

Within the model it was assumed that all appointments take place within GUM clinics. This was a simplifying assumption that is not expected to impact on the model results. In clinical practice, the majority of people with AGWs are treated in GUM clinics; however, a proportion of patients may be treated by their GP or in hospital. The proportion of people with AGWs treated in GUM clinics is reported by Lanitis51 to be 91% and by Desai et al. 3 to be 77%. Clinical expert opinion considered it likely that approximately 85–90% of appointments take place in GUM clinics, with the vast majority of the remainder carried out at GP practices and a minority carried out in hospital. The clinical experts approached considered that the proportion of patients treated in GUM clinics compared with GP practices would not differ by intervention. Consequently, the assumption that all appointments will be carried out in GUM clinics was not considered to be a key point of difference between interventions and is unlikely to affect the model results.

In clinical practice, all people with AGWs will experience a first appointment with a clinician to diagnose their AGWs; however, this appointment has not been modelled within the analysis. This is because the cost of attendance for the initial appointment will be the same for all interventions modelled and therefore will not affect the incremental results.

People treated first line with clinician-applied topical or ablative therapies, either as monotherapy or as part of a combination therapy, were assumed to require additional appointments in which the therapy is applied; the number of appointments was assumed to directly correlate to the number of required administrations, see Model structure. People treated with patient-applied topical therapy, or those who receive no treatment, were assumed to incur no additional appointments for application of their therapy.

All people with recurrence of AGWs after clearance with first-line treatment, or with AGWs that do not clear after first-line treatment, were assumed to return to their clinician and to incur the cost of an appointment. In contrast to the initial appointment, the cost of this appointment has been included in the analysis, because the number of required appointments will vary by treatment because of differences in rates of complete clearance at the end of treatment and rates of recurrence.

As with first-line treatment, people treated second line with clinician-applied topical or ablative therapies, either as monotherapy or as part of a combination therapy, were assumed to require additional appointments in which the therapy is applied; the number of appointments was assumed to directly correlate with the number of required administrations, see Model structure. People treated with patient-applied topical therapy were assumed to incur no additional appointments for application of their therapy.

Successful treatment of AGWs was assumed to result in no further appointments. Following review of the studies identified in the systematic review of the cost literature, it was noted that Woodhall et al. 176 reported that 45% of women and 55% of men attended their physician once (i.e. the initial appointment). Following consultation with clinical experts, it is considered likely that a majority of patients attending only once at the initial appointment are clear of AGWs and therefore chose not to return to the physician.

It was assumed that people who experience a recurrence of AGWs after second-line treatment, or who do not clear after second-line treatment, had persistent warts and a further two appointments are applied. As described above, this assumption is based on review of the study by Lanitis. 51

Cost of resources

The cost of attendance at a GUM clinic for an appointment was estimated by multiplying the estimated time per appointment by the cost of clinician time. The estimated time per appointment was taken from the study by Woodhall et al. 176 and costs for clinician time were taken from the Unit Costs for Health and Social Care 2013217 for community-based staff.

The study by Woodhall et al. 176 reported the results of a case note review of 370 people aged ≥ 16 years attending six sexual health clinics in England and one clinic in Northern Ireland. The authors recorded the resources used in the care of each participant and reported consultation times at clinics by staff involved in the visit. The estimates of consultation time were presented separately in the online appendix for women and men, by type of staff involved in the visit, by first and follow-up appointments and by laser treatment compared with all other treatments.

In the model, data for follow-up appointments were used. This is because the first appointment at a GUM clinic was not modelled (see Model structure). In addition, rather than modelling women and men separately, an average appointment time was calculated, which was weighted by the number of women (n = 157) and men (n = 213) surveyed.

The duration of appointment was assumed to differ by treatment administered. Specifically, the duration of appointment reported for laser therapy in Woodhall et al. 176 was used for appointments related to laser therapy, for appointments related to persistent warts and for appointments related to surgical excision. The duration of appointment reported for all other therapies in Woodhall et al. 176 was used for the remaining clinician-administered topical and ablative therapies.

For simplicity, it was assumed that, except for CO₂ laser therapy and surgical excision, the type of appointment (doctor led, nurse led or doctor with nurse) was equally split, that is, 33.3% doctor led, 33.3% doctor with nurse and 33.3% nurse led; for CO₂ laser therapy and surgical excision the split was 50% doctor led and 50% doctor with nurse. This was varied in sensitivity analysis.

The cost applied for a doctor and a nurse in the base case was £292 and £58 per hour, respectively. 217 The estimated weighted average cost per consultation for CO₂ laser therapy and surgical excision, and for appointments for persistent warts was £206.68. The estimated weighted average cost per consultation for all other treatments was £62.12. The consultation times and costs included in the analysis are presented in Table 41. Costs were varied in sensitivity analysis.

It was considered appropriate to apply the duration of appointment related to laser therapy in Woodhall et al. 176 to appointments related to persistent warts to reflect the increased likelihood that clinician-applied ablative therapies would be prescribed at this stage. Similarly, it was considered appropriate to apply the duration of appointment related to laser therapy in Woodhall et al. 176 to appointments related to surgical excision because surgical excision was considered by the clinical experts consulted to require a similar length of appointment to that for laser therapy in clinical practice.

Two other UK cost papers identified from the systematic review recorded an estimated time per appointment. 174,175 Both of these papers were published before that by Woodhall et al. 176 and involved review of the case notes for fewer people with AGWs (Woodhall et al. :175 189 people, published 2009; Langley et al. :174 200 people, published 2004; Woodhall et al. :176 370 people, published 2011). For these reasons, data from Woodhall et al. 176 were considered most appropriate for use within the model in the base case.