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Clinical trial A comparison of a 5% potassium hydroxide solution with a 5-fluorouracil and salicylic

Clinical trial

A comparison of a 5% potassium hydroxide solution with a 5-fluorouracil and salicylic acid combination in the treatment of patients with anogenital warts: a randomized, open-label clinical trial

Selda Is ik 1 , MD , Rafet Koca 2 , MD, G ulben

Sarici 3 , MD , and Hilmi Cevdet Altinyazar 4 , MD

1 Department of Dermatology, Faculty of Medicine, C anakkale Onsekiz Mart University, C anakkale, Turkey, 2 Department of Dermatology, Faculty of Medicine, B ulentEcevit University, Zonguldak, Turkey, 3 Department of Dermatology, State Hospital, Eskis ehir, Turkey, and 4 Department of Dermatology, Faculty of Medicine, Selc uk University, Konya, Turkey

Correspondence Rafet Koca, MD

B ulent

Deri ve Z uhrevi

Kozlu 67600 Zonguldak Turkey E-mails: rafkoca@yahoo.com, rafetkoca@karaelmas.edu.tr

Ecevit Universitesi Tıp Fak ultesi

Hastalıklar Anabilim Dalı

Conflicts of interest: None.

Abstract

Anogenital warts are caused by human papillomavirus (HPV), over 30 types of which are infectious for the anogenital tract. Without treatment, warts may regress spontaneously, remain unchanged, or increase in number and size. This study compared the efficacy of a topical 5% potassium hydroxide (KOH) solution with that of a topical 0.5% 5-fluorouracil (5-FU) and 10% salicylic acid (SA) combination in the treatment of anogenital warts. Sixty patients were randomly assigned to receive topical KOH or 5-FU + SA. Both groups demonstrated a significant decrease in numbers of lesions (P < 0.05), but this difference was not significant at week 12 ( P > 0.05). The mean number of lesions decreased from baseline to week 12 from 17.03 12.64 to 3.73 7.30 and from 16.13 12.97 to

3.10 4.90 in the KOH and 5-FU + SA groups, respectively ( P < 0.001). Excellent clearance was achieved by 70.0 and 76.7% of patients in the KOH and 5-FU + SA groups, respectively. Marked improvement was seen in 13.3 and 20.0% of patients in the KOH and 5-FU + SA groups, respectively. At week 16, relapse was observed in two patients in the KOH group and three in the 5-FU + SA group (P > 0.05). No serious adverse events were reported. Neither treatment was more efficacious. Safety and ease of application are important goals in treatments for anogenital warts. A 5% KOH solution is a promising alternative treatment because it is effective and inexpensive and causes minimal side effects.

Introduction

Anogenital warts are the most common of sexually trans- mitted infections worldwide. 1 They are caused by human papillomavirus (HPV), which is a double-stranded deoxy- ribonucleic acid (DNA) virus with more than 150 types. 2 More than 30 types of HPV are infectious for the anogeni- tal tract. 3 HPV-6 and HPV-11 are the causative types in 90% of cases. 4 In the USA, 3050% of sexually active adults are infected with HPV, but only 1% of them exhibit clinically visible genital warts. 5 Various options are avail- able for the treatment of external anogenital warts. Surgi- cal (cryotherapy, excision, laser therapy, electrosurgery) and non-surgical (trichloroacetic acid [TCA], imiquimod, podophyllotoxin) modalities can be applied. 6 Without treatment, warts may regress spontaneously, remain the same, or become more numerous and larger. 7 As they cause cosmetic and psychological discomfort, they reduce quality of life. Therefore, patients, as well as their part- ners, usually prefer the treatment option. 8 Low efficacy,

complications resulting from the treatments, and recur- rences are the problems most commonly associated with these treatment options. Hence, the most convenient ther- apeutic approach should be adopted for each patient. 7 9 Several articles have reported the efficacy of potassium hydroxide (KOH) solution in molluscum contagiosum and genital warts. 10 13 Although KOH solution appears to be an effective option for the treatment of genital warts, we were unable to find any studies in the literature in which it was compared with other effective therapies. Thus, the aim of the present study was to compare the efficacy and safety of topical 5% KOH solution with those of a topical 0.5% 5-fluorouracil (5-FU) and 10% salicylic acid (SA) combination in the treatment of anogenital warts.

Materials and methods

Study design

The study was approved by the Ethics Committee of the

Faculty of Medicine, B ulent

Ecevit University Hospital. All

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1146 Clinical trial KOH solution vs. 5-FU in anogenital warts

participants submitted signed written consent after being informed of the purpose and procedure of the study. This was a single-center, randomized, open-label study carried out to compare topical treatment with either 5% KOH or a 5-FU + SA combination (Verrutol ; Orva Pharma AS, Istanbul, Turkey) in patients with anogenital warts. A double-blind format was not used because one of the study medications (5-FU + SA) was a commercial product that was not label-blinded and because the study medications were packaged in containers of different sizes and shapes. Patients were randomly assigned to treatment with either a 5% KOH solution or a 5-FU + SA solution once daily for 12 weeks. Measurements were taken at baseline and at the end of weeks 1, 2, 4, 6, 8, and 12.

Patients

Patients were recruited from the Department of Derma- tology at BulentEcevit University. A total of 60 patients with diagnoses of genital warts, with one or more lesions, and aged 18 years were included in the study. All patients were Caucasian. Patients were required to com- plete a 3-month period of washout of topical wart ther- apy. Patients with any immunodeficiency, such as human immunodeficiency virus (HIV) infection, hepatitis B or C virus infection, syphilis, diabetes mellitus, malignancy, or giant genital warts, were excluded from the study. Patients who were pregnant or lactating were also excluded. Patients who were allergic to any of the compo- nents of the study medications were excluded. Patients were randomly assigned to receive topical 5% KOH solu- tion ( n = 30) or 5-FU + SA (n = 30) and instructed to apply the medication to the lesions once daily, in the evening, for 12 weeks. The topical 5% KOH solution was applied with a cotton applicator stick, and the 5- FU + SA combination was applied using its original appli- cator. In both groups, Vaseline was applied to the perile- sional area to minimize irritation. The same investigator carried out all evaluations at each visit. Anogenital warts were counted and photographed.

Randomization

Randomization was achieved using a simple randomiza- tion method in which random numbers were generated from a random table, and patients were allocated to receive either the topical 5% KOH solution or the 5-FU + SA combination.

Assessments

General patient data including demographic details and history of warts were recorded at baseline. The efficacy of the treatment was assessed by counting the number of papules. The primary efficacy endpoint was the change in papule counts from baseline to the last visit. Secondary efficacy parameters included changes in papule counts

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from baseline to each of weeks 1, 2, 4, 6, 8, and 12.

A physicians global assessment (PGA) of anogenital warts

was made using a 5-point scale at the endpoint (final assessment at week 12). The PGA index was rated as 1) excellent improvement indicated by regression of 76100%; 2) marked improvement indicated by regression of 5175%; 3)moderate improvement indicated by regres- sion of 26 50%; 4) insufficient improvement indicated by regression of 025%; or 5) deterioration). Should the =be removed from the multiple locations in this sentence? Recurrence was reassessed at week 16, one month after the completion of treatment. At any time during the treat- ment phase when no warts were visible, the use of test solutions was interrupted, and a control examination was subsequently performed by the investigator at the control weeks to assess any recurrence. Patients with warts that did not disappear during the 12-week treatment phase were excluded from the follow-up phase. New warts that appeared during the treatment period were treated with the study medication and included in the analysis.

Safety and tolerability

Treatment-emergent adverse events (AEs; pruritus, burn- ing, erythema, edema, erosions, and ulcerations) were recorded throughout the study period at each visit. Local reactions were graded as none, mild (minimal irritation), moderate (causing considerable discomfort), or severe. All safety analyses were conducted on an intention-to-treat basis.

Statistical analysis

The normality test of variables was performed using the Kolmogorov Smirnov test. Descriptive statistics for numerical variables are expressed as the mean standard deviation (SD). Categorical data are expressed as numbers and percentages. The correlations between categorical variables were examined using the chi-squared test. A comparison between the two groups of normally distrib- uted numerical variables used the t-test for determining the significance of the difference between two means; the MannWhitney U-test was used for non-normally distrib- uted numerical variables. The results were evaluated using 95% confidence intervals. SPSS Version 16.0 (SPSS, Inc., Chicago, IL, USA) was used for all analyses. A P-value of <0.05 was considered to indicate statistical significance.

Results

Patient characteristics

A total of 60 patients completed the study. Of the 30

patients in the KOH group, 22 (73.3%) were male and eight (26.7%) were female. Of the 30 patients in the 5-FU + SA group, 19 (63.3%) were male and 11 (36.7%)

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were female. The mean SD ages of participants in the KOH and 5-FU + SA groups were 37.00 9.51 years and 33.70 9.59 years, respectively. There were no significant differences in participant age or sex profiles between the two groups ( P > 0.05). The mean SD duration of lesions

and

11.07 16.62 months in the 5-FU + SA group. The mean SD number of lesions was 17.03 12.64 and 16.13 12.97 in the KOH and 5-FU + SA groups, respec- tively. There were no significant differences between the two groups in the duration or number of lesions ( P > 0.05). Demographic data for both groups at baseline are summarized in Table 1.

was 13.57 14.35 months in the KOH group

Assessment of efficacy

Both treatment groups demonstrated a significant decrease in the number of lesions during the treatment period ( P < 0.05), but the difference between treatments was not significant at the end of week 12 (P > 0.05). The mean SD number of lesions decreased from 17.03 12.64 at baseline to 3.73 7.30 at week 12 and from 16.13 12.97 at baseline to 3.10 4.90 at week 12 in the KOH and 5-FU + SA groups, respectively ( P < 0.001; Fig. 1, Table 2). There were no significant dif- ferences between treatments in mean lesion counts at any evaluation visit during the study (P > 0.05 for each time- point). The PGA of anogenital warts was assessed at the study endpoint. Excellent clearance was achieved by 70.0% of patients in the KOH group and 76.7% of those in the 5-FU + SA group. Marked improvement was seen in 13.3% of patients in the KOH group and 20.0% of patients in the 5-FU + SA group (Fig. 2). Although the number of patients showing complete or marked improvement was greater in the 5-FU + SA group, there were no significant differences between the treatments in PGA at the end of the study (P > 0.05).

Table 1 Demographics and baseline characteristics of patients with anogenital warts treated with a 5% potassium hydroxide (KOH) solution or a 0.5% 5-fluorouracil plus 10% salicylic acid (5-FU + SA) solution

Patient characteristics

5% KOH group ( n = 30)

5-FU + SA group ( n = 30)

Age, years, mean SD Gender, n (%) Male Female Disease duration, months, mean SD Lesion count, mean SD

37.00 9.51

33.70 9.59

22 (73.3) 8 (26.7) 13.57 14.35

19 (63.3) 11 (36.7) 11.07 16.62

17.03 12.64

16.13 12.97

SD, standard deviation.

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18.00 KOH 16.00 5-FU + SA 14.00 12.00 10.00 8.00 6.00 4.00 2.00 0.00 Baseline
18.00
KOH
16.00
5-FU + SA
14.00
12.00
10.00
8.00
6.00
4.00
2.00
0.00
Baseline
1
2
4
6
8
12
Mean papule count

Week

Figure 1 Reduction in mean lesion counts among patients with anogenital warts treated with a 5% potassium hydroxide (KOH) solution or a 0.5% 5-fluorouracil plus 10% salicylic acid (5-FU + SA) solution ( n = 30 in each group)

Table 2 Lesion counts over the course of treatment in patients with anogenital warts treated with a 5% potassium hydroxide (KOH) solution or a 0.5% 5-fluorouracil plus 10% salicylic acid (5-FU + SA) solution

Lesion count, mean SD

Week

5% KOH group ( n = 30)

5-FU + SA group ( n = 30)

P -value

0

17.03 12.64

16.13 12.97

0.786

1

13.77 10.40

12.33 11.63

0.617

2

10.87 9.96

9.80 10.28

0.685

4

7.00 8.59

7.17 8.33

0.939

6

5.57 7.82

5.00 5.80

0.751

8

5.50 7.85

4.63 6.40

0.641

12

3.73 7.30

3.10 4.90

0.695

At the end of week 16, relapse was observed in two patients in the KOH group and three patients in the 5-FU + SA group. There were no significant differences between the two groups in the number of relapses (P > 0.05). Figure 3 shows pre- and post-treatment clini- cal photographs of patients in the KOH group.

Safety and tolerability

The topical preparations of both medications were well tolerated. No serious or systemic AEs were reported in either treatment group. The most common treatment- related cutaneous AEs were a burning sensation and ero- sion in both groups. These AEs were mild and transient in nature. In the event of an AE, treatment was suspended for a few days and then continued. Patients described

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both treatments as acceptable in terms of local tolerabil- ity. None of the patients discontinued the study because of AEs.

Discussion

This randomized study compared the efficacy and safety of a 5% KOH solution with that of 0.5% 5-FU and 10% SA combination therapy in patients with anogenital warts. Both topical preparations led to a clinically rele-

90 80 70 60 KOH 5-FU + SA 50 40 30 20 10 0 Excellent
90
80
70
60
KOH
5-FU + SA
50
40
30
20
10
0
Excellent
Marked
Moderate
Insufficient
Deterioration
Percentage of patients

Figure 2 Global assessment at the end of therapy in patients with anogenital warts treated with a 5% potassium hydroxide (KOH) solution or a 0.5% 5-fluorouracil plus 10% salicylic acid (5-FU + SA) solution ( n = 30 in each group; P > 0.05)

vant improvement in lesions. We found that after 12 weeks of treatment, the 5% KOH solution was no more efficacious than the 5-FU + SA combination in treating anogenital warts. Both treatments are equally effective in reducing the number of inflammatory lesions. Both treatment groups experienced a continuous decline in mean lesion counts throughout the 12 weeks. The treatment of genital warts constitutes a consider- able burden to patients as well as to physicians. Most current treatment modalities are painful, prolonged, and expensive, and the disease is highly recurrent. 9 Although there are many treatment modalities, none of them offer 100% satisfaction. 14 As the eradication of HPV is so dif- ficult, the main goal of treatment is to remove clinically visible warts. 15

Primarily, the patient s preference should be the deter-

mining factor in the choice of treatment. This is because none of the options is superior to the others, and all treat- ment options have variable effects. Options associated with higher costs, scarring, and toxicity should be ignored. Standard treatments can be classified as patient- applied treatments (podofilox 0.5%, imiquimod cream 5%, topical 5-FU) or as physician-applied treatments (cryotherapy, application of podophyllin 10 25%, tri- chloroacetic acid, or bichloroacetic acid, intralesional interferon, systemic interferon, surgical excision, electro- surgery, and laser surgery). As physician-applied treat- ments are more invasive and cost more, both physicians

(a) (c) (b) (d)
(a)
(c)
(b)
(d)

Figure 3 (a, b) Before and (c, d) after 12 weeks of treatment with the 5% potassium hydroxide (KOH) solution

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and patients primarily prefer patient-applied treat- ments. 4,16,17 Consequently, many physicians seek new therapeutic alternatives for the treatment of anogenital warts. Potassium hydroxide is an alkali that affects the skin by dissolving keratin. Because of this characteristic, it is mostly used to identify dermatophytes. It has begun to be used in various diseases, such as molluscum contagiosum. Romiti et al. 10 found that 10% KOH solution was effec- tive and safe in the treatment of children with molluscum contagiosum. However, KOH solutions can cause varying degrees of irritation depending on their concentration. The 5% concentration is found to be as effective as the 10% solution and has fewer side effects. 10 12 Satisfactory outcomes of the use of KOH solutions in the treatment of molluscum contagiosum have led physicians to apply these solutions in the treatment of genital warts. Loureiro et al. 13 reported that the 5% KOH solution was effective and safe in a trial including 35 men with external genital warts. At the end of the study, 87.5% of patients showed full recovery. 13 At one month after the completion of treatment, recurrence was observed in 9.0% of patients. 13 Reports suggest that recurrent administrations carry no risks and that administrations can be repeated in the event of recurrence. 13 Medications containing 5-fluorouracil have been reported to be effective in the treatment of genital and extragenital warts. 18,19 Salicylic acid increases the penetration and effi- cacy of 5-FU because it is keratolytic in nature. We com- pared a topical KOH solution and topical 5-FU + SA combination that is commercially available in Turkey (Verrutol ; Orva Pharma AS) as a patient-applied option. No serious or systemic AEs were reported in either treatment group. Eighteen of the 30 patients who received the 5% KOH solution demonstrated erythema and a burning sensation. These events were mild and transient in nature, and patients continued with treatment because it proved effective. The most common side-effect of the KOH solution was reported to be a transient burning sen- sation and irritation. The irritation caused by a KOH solution depends on its concentration. 11,12 There were no significant differences between treatments in term of AEs at any evaluation time-point during the study. The present study is subject to several limitations: it was not a double-blind study, and its follow-up period was inadequate. In general, genital warts subjected to any treat- ment modality show recurrence rates of 3070% during a 6-month follow-up period. 20 We followed our patients for one month and identified new warts in two patients in the KOH group and three patients in the 5-FU + SA group. However, we concluded that this problem arose as a result of the natural course of the virus rather than the method employed. In fact, it is nearly impossible to differentiate

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relapse (reappearance of treated warts) from reinfection (new warts in new locations). This is also true when the condition is treated with other modalities. In conclusion, 5% KOH solution is not more effica- cious than a 5-FU + SA combination in the treatment of anogenital warts. Safety and ease of patient application are important goals in treatments for anogenital warts. A 5% KOH solution is a promising alternative treatment for anogenital warts because it is effective, causes mini- mal side effects, and is available at a low cost.

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