Combined treatment of anogenital HPV infection with cryodestruction,podophyllin 25% and post-ablation immunomodulation with sinecatechins 15% ointment

Abstract

External genital warts, caused by human papillomavirus, have a significant clinical, epidemiological, and financial impact, including the risk for malignant transformation. Treatment modalities include: (a) destructive (ablative); (b) cytotoxic (proapoptotic) and (c) immunomodulatory, with success and recurrence rates varying from 23% to 94% and from 4.1% to 77%, respectively. Most studies evaluated only single modality therapy, with few reports examining a combined approach for external genital warts management. The introduction of sinecatechins ointment in recent years has resulted in very low recurrence rates of 4.1–10.6%, despite lower initial clearance rates than ablative methods. We present a retrospective review of 27 patients who underwent combined therapy for external genital warts by using one or two sessions of cryodestruction combined with 25% podophyllin as the cytotoxic agent, and post-ablation immunomodulation with topical sinecatechins 15% ointment. This approach resulted in an excellent initial clearance rate of 96.3% with a recurrence rate of 7.4% after a total period of six months of follow-up. We suggest the importance of the combined approach in external genital warts management including post-ablative immunomodulation to augment the immune response and combat the residual latent infection. We hope to encourage trials examining the combined approach to the treatment of external genital warts.

Keywords

HPV genital warts treatment cryodestruction immunomodulation sinecatechins

Introduction

External anogenital warts (EGWs) are benign tumours caused by an infection with more than 40 types of human papillomavirus (HPV), most commonly ‘low-risk’ types 6 and 11. EGWs affect 1% of the sexually active population aged 15–49 per year with more than one million new cases annually. Furthermore, approximately 15% of adults are suspected to have subclinical infections.^1–5 Apart from ‘low-risk’ HPV infection, ‘high-risk’ strains 16, 18, 31, 33 and 35 are known to be associated with dysplasia and carcinoma.⁶

The molecular mechanism of progression and persistence of a HPV infection has recently been elucidated, providing a basis for understanding the survival of HPV and its evasion of the immune response. The virus exclusively infects the basal cells of the epithelium/epidermis following microtrauma and persists in the nucleus in the form of an episome with replication controlled by the E2 protein.⁷ Furthermore, other early protein products like E6 and E7 are strong inhibitors of p53 (induces apoptosis) and retinoblastoma protein (Rb – regulates transcription), respectively, thus enabling uncontrolled proliferation of the virus and survival of HPV-infected cells.⁷ An infection with HPV also has profound immune-dysregulatory effects such as the inhibition of interferon response, down regulation of the CD95 receptor (apoptosis resistance) and reduction in antigen presentation by blocking intracellular antigen processing machinery.⁷ The absence of cytolysis, cytopathic effects and inflammation fails to trigger danger signals that would customarily induce the innate or adaptive immune response. Other mechanisms like T-cell polarisation (Th1–Th2 switch), inhibition of the cytotoxic T-cell response, as well as down regulation of antigen-presenting cell (APC) trafficking further contribute to the prolonged persistence of the infection in the suprabasal environment, far from the subepidermal immune milieu of dendritic cells, macrophages and lymphocytes.⁷ The proliferation of HPV-infected squamous cells that are normally in the post-mitotic phase (in the absence of a HPV infection) slowly builds up to clinically visible lesions. The shedding of infected cells and viral particles from the corneal layer further spreads the virus to surrounding areas of the skin/mucosa of the host or his/her partner via microtraumas of the surface of the skin/mucosa. After years of persistence, malignant subtypes have the potential to integrate in the host genome and produce malignant transformation, i.e. squamous cell dysplasia, carcinoma in situ or invasive carcinoma.

The goals of treatment include removal of warts and prevention of future recurrences.^2,4,6 Treatment of EGWs can be administered by the patient or physician and includes the following categories: (1) antiproliferative (proapoptotic) agents (podophyllin resin 10–25%, podofilox/podophyllotoxin 0.5% solution; 5-fluoruracil, bleomycin); (2) destructive/excision techniques (cryosurgery, electrosurgery, laser ablation, surgical resection); (3) immunomodulatory agents (interferon, imiquimod 3.75% or 5% cream and sinecatechins green tea extract as 15 or 10% ointment in USA and Europe, respectively [Table 1]). The reported clearance rates (CRs) range from 23% up to 94%, with cryosurgery, electrosurgery and antiproliferative agents having the highest rates of success as a single modality.⁸ Unfortunately, most of the clinician-applied techniques carry a high recurrence rate (RR) in the 12–16 weeks after therapy, varying from 18% up to 77% for some modalities like CO₂ laser ablation.⁸ The HPV particles in the smoke released during tissue vaporisation (laser or electrosurgery) have potential to infect adjacent skin, if its integrity is compromised either by the presence of abrasions, microtrauma or the ablative procedure itself.⁹ On the contrary, immunomodulatory therapies, despite lower initial CR (28% to 57.2%), have higher sustained clearance with RR from 15% (imiquimod) to as low as 4.1–8.3% (sinecatechins) in the 12–16-week follow-up periods.^2,3,10 Topical imiquimod use has been associated with loss of pigment, severe inflammation, and discomfort in the treated area.^8,10 Sinecatechins, a green tea leaf derivative, is another compound with possible immunostimulatory, antiviral and antiproliferative activity.¹¹ It was approved as 15% ointment, for the US market in 2006¹ and subsequently in Europe and Canada as a 10% ointment. The sustained CR above other patient-applied EGW therapies, as well as a tolerable side-effect profile, has made it an important addition to patient-applied treatment modalities^1–3 with no clinically relevant difference among the 10% and 15% concentration regarding the CR, RR, efficacy and tolerability.²

Table 1.

Treatment options for anogenital HPV disease.

Treatment	Description	Mode of action	Clearance rate (%)	Recurrence rate (%)	Reference
Podofilox/podophyllotoxin 0.5% solution	Antimitotic agent	Induces tissue necrosis	45–77	38–65	Lacey et al.²²
Imiquimod (Aldara) 5%	Immunomodulatory	Stimulates production of interferon and cytokines	50–52	13–19	Edwards et al.²⁰, Beutner et al.²¹
Imiquimod 3.75%	Immunomodulatory	Stimulates production of interferon and cytokines	28–33	15	Vender et al.⁸
Podophyllin	Antimitotic agent	Induces tissue necrosis	37–63	44–60	von Krogh and Longstaff²³, Stone et al.²⁴
Trichloroacetic acid	Acid	Produces a chemical burn	70	18	Taner et al.²⁵
Sinecatechins 15% (USA) and 10% (Europe, Canada)	Botanical extract	Antiviral, immunostimulatory, antiproliferative	50.8–57.2	4.1–8.3	Tatti et al.², Stockfleth et al.³ and Rosen¹¹
Surgical excision	Scissor or scalpel excision	Removal of affected tissue	72	19–29	Vender et al.⁸
Electrosurgery	High-frequency electrical currents	Thermal damage	94	22	Stone et al.²⁴
Cryodestruction	Nitrous oxide or liquid nitrogen to ‘freeze’ affected skin tissue	Destruction of affected tissue via freezing	79–88	25–39	Scheinfeld and Lehman⁹
CO2 laser therapy	Infrared light energy	Vaporises skin cells	23–52	60–77	Duus et al.²⁶

Due to the lack of properly designed combination therapy trials for EGWs¹² and a need to obtain better sustained long-term clearance of EGWs, the standard approach in our practice has become a combination of destructive (cryosurgery), and antiproliferative-proapoptotic (podophyllin 25%) modality, followed by a patient-applied agent with immunomodulatory properties (sinecatechins 15% ointment).

To our knowledge, no studies have been done to evaluate the addition of sinecatechins to cryodestruction with podophyllin application. The purpose of this retrospective chart review was to evaluate the CR and RR of this combination approach for the follow-up period of six months following completion of the treatment.

Patients and methods

Our review consisted of male and female patients aged 18–65 years with a first-time diagnosis of anogenital HPV disease, not previously treated, in good general health (determined by history, physical examination and basic chemistries) and immunocompetent. All patients were advised to use condoms or were abstaining from sexual intercourse during the treatment. All female patients had to have one negative pregnancy test and use contraception as well as barrier protection (condom). All pregnant or breast-feeding women as well as individuals with cardiac, pulmonary, renal or other chronic disease were excluded from the study. Clinical criteria for enrolment were the presence of 2–20 individual anogenital lesions with a maximal wart-affected area of less than 10 cm².

Figure 1.

Hallmark of our technique – immediate application of podophyllin 25% to freshly frozen genital warts (a). Flow diagram of treatment protocol (b).

Treatment protocol

See Figure 1(a) and (b). The patients were treated initially with cryodestruction of all affected lesions using an open-spray technique, with 20–30 s of direct freeze, in two cycles after 40–60 s of thaw time (Cryogun, Brymill, CT). Upon completion of freezing, all affected areas were painted with 25% podophyllin in benzoic tincture, with maximal surface of application always less than 10 cm², and total amount of solution 0.5 cc or less according to FDA guidelines (Figure 1(a)). Patients were advised to wash the treated area with soap and water after six hours following podophyllin application. Two weeks following the cryodestruction, patients started to apply sinecatechins 15% ointment (Veregen© (sinecatechins) ointment 15%, Pharmaderm, Melville, NY, USA) 3×/daily until the lesions were completely cleared or side effects developed for the maximal period of 12–16 weeks. The monitoring of side effects consisted of regular inquiries on the development of erythema, oedema, pain, burning, dyspareunia, vesiculation, erosion, crusting, scarring or other symptoms reported by the patient. Photographic documentation was made during the first visit and at four-week intervals thereafter until the completion of the six months of follow-up (Figure 1(b)). Baseline warts were designated as ones present at the first visit, persistent warts were those which did not resolve completely following the second round of treatment and recurrent warts were those that initially cleared and then recurred during the follow-up period. In persistent and recurrent cases, the patient underwent another session of cryodestruction/podophyllin four weeks after the initial one followed by application of sinecatechins 15% ointment, two weeks later, using the same protocol as above. Patients were followed up for a total of six months, with monthly intervals.

Statistical analysis

The statistical analyses were performed using MiniTab 16.0 statistical software. The χ² test (factoring in Yates’s Correction for Continuity) was utilised for finding differences in two categorical proportions. The combined treatment of anogenital HPV infection with cryodestruction, podophyllin and immunomodulation with sinecatechins 15% ointment was individually compared with referred single modality reviews for (Table 3) cryodestruction, podophyllin 25% and sinecatechins 15%.⁸ A p value < 0.05 specified that the two samples differed statistically.

Results

The retrospective chart review comprised a total of 27 patients, 23 men and four women, in a four-year retrospective evaluation from January 2010 to January 2014. Patient age was from 19 to 45 years, and after six months, two out of 27 patients developed recurrent disease. One of these patients also had persistent warts after initial therapy as well as recurrent lesions, at sites where warts had temporarily resolved. Sixteen patients required a second cryosurgery/podophyllin session, and 25 of 27 patients were able to continue sinecatechins 15% ointment until the complete clearance of the warts. However, the total of duration of 16 weeks was not found to be necessary in many patients, with the average length of application being eight weeks post cryodestruction. Only two patients stopped sinecatechins 15% ointment after four weeks, and failed to complete treatment due to a severe inflammatory reaction with severe oedema and vesiculation. However, they did not have recurrent disease at the end of the follow-up period. Six patients had milder side effects (erythema, mild oedema, itching and no erosions) and were able to continue sinecatechins 15% ointment after a one-week break following the initial four weeks of therapy, and subsequently tolerated the application until complete clearance of the warts. Two complete rounds of treatment with cryotherapy, podophyllin and sinecatechins therapy led to complete clinical clearance in all but one treated individual. All patients with recurrent or persistent disease were also noted to have been smokers with >10 cigarettes daily for at least 10 years before the presentation (Table 2).

Table 2.

Demographic and clinical data of patients in our study.

Patient	Sex	Age	Smoker (yes/no)	Location (vulva, penis)/ perianal	Cryosurgery/ podophyllin sessions	Sinecatechins application		Clearance	Recurrence or persistence
Patient	Sex	Age	Smoker (yes/no)	Location (vulva, penis)/ perianal	Cryosurgery/ podophyllin sessions	Weeks	Side effect	Clearance	Recurrence or persistence
1	F	31	No	Vulva	2	4 + 4	Erythema	Yes	No
2	M	26	No	Penis	2	4 + 4	Erythema	Yes	No
3	M	38	Yes	Perianal	1	10	Erythema, oedema	Yes	No
4	M	26	No	Penis	1	8	Erythema, pruritus	Yes	No
5	M	41	Yes	Penis	2	4 + 4	Erosions	Yes	Recurrence
6	F	38	No	Vulva	1	6	Erythema	Yes	No
7	M	27	No	Penis	2	4 + 4	Erythema	Yes	No
8	M	27	No	Penis	2	4 + 4	Erythema	Yes	No
9	F	45	Yes	Vulva	2	4 + 4	Erythema, oedema	Yes	No
10	F	45	No	Perianal	1	4	Vesiculation, oedema	Yes	No
11	M	45	No	Penis	1	4	Vesiculation, oedema	Yes	No
12	M	29	No	Penis	2	4 + 4	Pruritus	Yes	No
13	M	42	No	Penis	1	6	Erythema, oedema	Yes	No
14	M	33	No	Penis	2	4 + 4	Erythema	Yes	No
15	M	34	No	Penis	1	6	Erythema	Yes	No
16	M	27	No	Penis	2	4 + 4	Pruritus, oedema	Yes	No
17	M	19	No	Penis	2	4 + 4	Erythema, oedema	Yes	No
18	M	23	Yes	Penis, perianal	2	4 + 4	Erythema	Yes	Recurrence
19	M	42	Yes	Penis	2	4 + 10	Erythema, oedema	No	Persistence
20	M	29	No	Perianal	1	8	Erythema, oedema	Yes	No
21	M	26	No	Penis	1	6	Erythema, pruritus	Yes	No
22	M	26	No	Penis	1	8	Erythema, oedema	Yes	No
23	M	26	No	Penis	2	4 + 4	Erythema	Yes	No
24	M	45	No	Penis	1	8	Erythema, oedema	Yes	No
25	M	28	No	Penis	2	4 + 4	Erythema	Yes	No
26	M	26	No	Perianal/penis	2	4 + 4	Erythema	Yes	No
27	M	19	No	Penis/perianal	2	4 + 4	Erythema	Yes	No

Table 3.

Comparative analysis of success rates for single vs. combined therapies for anogenital HPV disease.

Treatment	Clearance rate (%)	Recurrence rate (%)	Duration of treatment (weeks)	References
Cryodestruction	79–88	25–39	3.8 (once a week)	Scheinfeld and Lehman⁹
Podophyllin 25%	37–63	44–60	4.2 (once or twice weekly)	von Krogh and Longstaff²³, Stone et al.²⁴
Sinecatechins 15%	52.6–59	5.9–10.6	Up to 12–16 (3×/day)	Tatti et al.,² Stockfleth et al.,³ Tatti et al.⁴ and Gross et al.⁵
Cryodestruction vs. combined cryodestruction and sinecatechins 15% ointment	28.6 vs. 28.6 (complete clearance)	52 vs. 71 (partial clearance)	Single session cryodestruction or combined with 12–16 weeks sinecatechins 15% 3×/day	On et al.¹⁹
Our study	96.3	7.4	Once a month, two sessions maximum, plus up to 12–16 weeks sinecatechins 15% 3×/day

The combined treatment of anogenital HPV infection with cryodestruction, podophyllin and immunomodulation with sinecatechins 15% ointment significantly outperformed both podophyllin 25% (p < .001) and sinecatechins 15% (p = .003) single modality approaches from previous studies in CR. It also had lower RR vs. podophyllin 25% (p = .002) or cryoablation monotherapy (p = .0090). Statistical significance was not shown in RR between combined approach and sinecatechins 15% monotherapy (p = .7047) as well as in CR of combined treatment method vs. cryodestruction monotherapy (p = .1094); however, the RR was significantly less when combined treatment method was compared to cryodestruction monotherapy (p = .0090). In all instances, the combined treatment method significantly outperformed the single modality approaches in at least one aspect indicating that combined treatment may be a better alternative to single modality approaches.

Discussion

Four traditional goals for the treatment of sexually transmitted infections (STIs), i.e. eradication of infection, elimination of symptoms, prevention of long-term sequelae and interruption of transmission are hard to achieve with EGWs. In order to completely clear the infection, one would need to eliminate the bulk of the visible disease as well as the subclinical infection in basal cell of the epidermis/epithelium where HPV persist in a form of episomes.⁷ The treatment should start as early as possible, to prevent integration of the HPV DNA into the nuclear DNA, after which it becomes virtually undetectable for the immune system.⁷ Furthermore, the chosen treatment should enhance conditions for improved immune surveillance, by releasing ‘danger signals’ into the condyloma lesions, and as such improve the recognition of the viral epitopes by dendritic cells, thus stimulating the protective immune response. In addition, the applied therapies should theoretically minimise induction of any kind of trauma to surrounding healthy epidermis, since released HPV virions (e.g. from the plumes of laser or electrosurgery) could result in areas of new infection or re-infection. These goals are difficult to simultaneously achieve with monotherapy, it being either patient or physician-applied.

Our debulking treatment of choice was cryodestruction, since it does not require anaesthesia, does not produce plumes loaded with viral particles (electrosurgery or CO2 laser vaporisation) and does not require specialised equipment or conditions like surgical excision. Additionally, cryosurgery has very well-known immune-stimulatory effects by destroying a portion of the infected keratinocytes, thus providing danger signals of inflammation upon direct cell damage and vascular effects produced by reported freezing temperatures of −20 to 25 ℃.¹³ Podophyllin resin works as an antimitotic agent, has a low cost, is easy to apply, and has mild side effects if applied correctly, avoiding eroded or ulcerated areas, the anal canal, vaginal mucosa or the urethra.⁸ We chose podophyllin since this treatment is physician applied and could be done in a controlled manner in the office; it also allowed the patient to be properly instructed in aftercare. Additionally, application immediately upon cryosurgery has potential adjuvant effects and better penetration, increasing the likelihood of eradication of residual HPV-infected proliferating cells from basal or suprabasal cell layers in the surrounding skin/mucosa.¹⁴ Combined with cryodestruction, podophyllin application to the lesions and surrounding areas has also been shown to reduce the number of treatment sessions when compared with the use of each modality alone to 1.9 from 4.2.¹⁵ The majority of our patients had complete clinical response after two rounds of combined treatment. Thirdly, the use of an immunomodulatory agent should follow any successful clinical treatment of condylomas to improve immune surveillance and decrease the risk of recurrence by acting on the remaining infected keratinocytes. Our preference of sinecatechins 15% ointment over imiquimod was due to a lack of reports of systemic side effects as well as the absence of risk for hypopigmentation, which may be permanent in some cases.¹⁶ The exact mechanism of action of green tea catechins in clinical settings is currently unknown, but seems to be based on antiviral, antiproliferative and immunostimulatory properties shown in many in vitro studies.¹¹ Antiviral activity is based on the inhibition of viral gene expression, including cell-cycle regulators and viral kinases. Immunostimulatory effects comprise cyclooxygenase inhibition (COX-2), stimulation of the release of immunostimulatory cytokines like interleukins (IL-12), tumour necrosis factor (TNF-α) and interferon (IFN-γ), as well as the reduction of immunosuppressive IL-10 concentration.^8,11,17

Three patients who had persistent or recurrent disease were heavy smokers. The association of smoking and HPV infection is well recognised. Indeed, one study showed that 23% of smokers have EGWs, as well as higher RR.¹⁸ Carcinogens from tobacco can be detected downstream in the genital area causing stable DNA adducts, modulating inflammation-induced metaplasia and causing apoptosis in both humoral and cellular immune response pathways.¹⁸ Hence, the strict cessation of smoking should always be considered for any patient with anogenital HPV disease.

In our review of the literature, we were able to find one study which combined cryodestruction with topical sinecatechins 15% ointment.¹⁹ The authors randomised patients in two groups: the first group received a single-session cryodestruction alone, while the second group was treated with cryodestruction followed by 12–16 weeks of sinecatechins 15% ointment. There was no difference among the groups in complete CR (28.6% vs. 28.6%); however, more favourable responses were seen in partial clearance for the anogenital warts in the combined cryodestruction/sinecatechins group (71% vs. 52%) after 16 weeks of application. Despite the long follow-up period of 68 weeks, this study is limited by treatment with a single freezing session and a short cryogen application time (5 s) with short thawing interval (5 s), which could have contributed to less favourable outcomes.

In conclusion, we present a retrospective case series on the combined treatment of anogenital HPV infection with cryodestruction, podophyllin and post-ablative immunomodulation with sinecatechins 15% ointment. The initial complete CR of 96.3%, altogether with the RR of 7.4%, is significantly better when compared to reported success for monotherapies (Table 3). The main weakness of our study is its retrospective design, and statistical analysis based on comparison of our results with treatment data from previous single modality reports.

We hope to encourage randomised controlled trials where the combined treatment approach with post-ablation immunomodulation is used to obtain better control of the burden of anogenital HPV disease.

Figure 2.

Patient #9 with large vulvar condylomas before treatment (a) and three months after completion of the second session (b).

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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Combined treatment of anogenital HPV infection with cryodestruction,podophyllin 25% and post-ablation immunomodulation with sinecatechins 15% ointment – a retrospective analysis

Abstract

Keywords

Introduction

Patients and methods

Treatment protocol

Statistical analysis

Results

Discussion

Footnotes

Declaration of Conflicting Interests

Funding

References