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 Isik1, MD, Rafet Koca2, MD, G
ulben Sarici3, MD, and Hilmi Cevdet Altinyazar4, MD

1
Department of Dermatology, Faculty of
Medicine, C
anakkale Onsekiz Mart
University, C
anakkale, Turkey, 2Department
lent
of Dermatology, Faculty of Medicine, Bu
Ecevit University, Zonguldak, Turkey,
3
Department of Dermatology, State
Hospital, Eskisehir, Turkey, and
4
Department of Dermatology, Faculty of
Medicine, Selcuk University, Konya, Turkey

Correspondence
Rafet Koca, MD

lent Ecevit Universitesi

ltesi
Bu
Tp Faku
hrevi Hastalklar Anabilim Dal
Deri ve Zu
Kozlu 67600
Zonguldak
Turkey
E-mails: rafkoca@yahoo.com,
rafetkoca@karaelmas.edu.tr

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

Conflicts of interest: None.

alternative treatment because it is effective and inexpensive and causes minimal side
effects.

Introduction
Anogenital warts are the most common of sexually transmitted infections worldwide.1 They are caused by human
papillomavirus (HPV), which is a double-stranded deoxyribonucleic acid (DNA) virus with more than 150 types.2
More than 30 types of HPV are infectious for the anogenital 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 available for the treatment of external anogenital warts. Surgical (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 partners, usually prefer the treatment option.8 Low efficacy,
2014 The International Society of Dermatology

complications resulting from the treatments, and recurrences are the problems most commonly associated with
these treatment options. Hence, the most convenient therapeutic approach should be adopted for each patient.79
Several articles have reported the efficacy of potassium
hydroxide (KOH) solution in molluscum contagiosum and
genital warts.1013 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
lent Ecevit University Hospital. All
Faculty of Medicine, Bu
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1145

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 Dermatology at B

ulent Ecevit 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 complete a 3-month period of washout of topical wart therapy. 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 components of the study medications were excluded. Patients
were randomly assigned to receive topical 5% KOH solution (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 5FU + SA combination was applied using its original applicator. In both groups, Vaseline was applied to the perilesional 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 randomization 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
International Journal of Dermatology 2014, 53, 11451150

Is ik et al.

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 76
100%; 2) marked improvement indicated by regression of
5175%; 3)moderate improvement indicated by regression of 2650%; 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 treatment 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, burning, 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

KolmogorovSmirnov 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 distributed 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 distributed 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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Is ik et al.

KOH solution vs. 5-FU in anogenital warts

18.00
KOH

16.00

5-FU + SA
14.00

Mean papule count

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
was 13.57  14.35 months in the KOH group 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, respectively. 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.

12.00
10.00
8.00
6.00
4.00
2.00
0.00
Baseline

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 differences between treatments in mean lesion counts at any
evaluation visit during the study (P > 0.05 for each timepoint).
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

Age, years, mean  SD

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

12

Week

Assessment of efficacy

Patient characteristics

Clinical trial

5% KOH group
(n = 30)

5-FU + SA group
(n = 30)

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.

2014 The International Society of Dermatology

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)

0
1
2
4
6
8
12

17.03
13.77
10.87
7.00
5.57
5.50
3.73









12.64
10.40
9.96
8.59
7.82
7.85
7.30

5-FU + SA group
(n = 30)
16.13
12.33
9.80
7.17
5.00
4.63
3.10









12.97
11.63
10.28
8.33
5.80
6.40
4.90

P-value
0.786
0.617
0.685
0.939
0.751
0.641
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 clinical 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 treatmentrelated cutaneous AEs were a burning sensation and erosion 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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Clinical trial

KOH solution vs. 5-FU in anogenital warts

both treatments as acceptable in terms of local tolerability. 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 rele90
80

Percentage of patients

1148

70
60

KOH
5-FU + SA

50
40
30
20
10
0

Excellent

Marked

Moderate

Insufficient Deterioration

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)

(a)

(b)

Is ik et al.

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 considerable 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 difficult, the main goal of treatment is to remove clinically
visible warts.15
Primarily, the patients preference should be the determining factor in the choice of treatment. This is because
none of the options is superior to the others, and all treatment options have variable effects. Options associated
with higher costs, scarring, and toxicity should be
ignored. Standard treatments can be classified as patientapplied treatments (podofilox 0.5%, imiquimod cream
5%, topical 5-FU) or as physician-applied treatments
(cryotherapy, application of podophyllin 1025%, trichloroacetic acid, or bichloroacetic acid, intralesional
interferon, systemic interferon, surgical excision, electrosurgery, and laser surgery). As physician-applied treatments are more invasive and cost more, both physicians

(c)

(d)

International Journal of Dermatology 2014, 53, 11451150

Figure 3 (a, b) Before and (c, d) after

12 weeks of treatment with the 5%
potassium hydroxide (KOH) solution
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Is ik et al.

and patients primarily prefer patient-applied treatments.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 effective 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.1012 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 efficacy of 5-FU because it is keratolytic in nature. We compared 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 sensation 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 treatment 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
2014 The International Society of Dermatology

KOH solution vs. 5-FU in anogenital warts

Clinical trial

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 efficacious 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 minimal side effects, and is available at a low cost.

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2014 The International Society of Dermatology