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 Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 28  |  Issue : 2  |  Page : 367-371

The use of podophyllotoxin for treatment of genital warts


1 Dermatogy, Andrology and S.T.Is Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Dermatogy, Andrology and S.T.Is Department, Quwesna Hospital, Shebin El-Kom, Egypt

Date of Submission12-May-2014
Date of Acceptance09-Jul-2014
Date of Web Publication31-Aug-2015

Correspondence Address:
Samar M Fakhrey Abd El-Motaleb
Sheben El-Kom, Menoufia 32511
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.163886

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  Abstract 

Objective
The aim of the study was to determine the clinical profile of genital warts (GWs) among Egyptians and evaluate the therapeutic effect of podophyllotoxin.
Background
External GWs are caused by proliferation of squamous epithelial cells secondary to human papillomavirus infection. It is sexually transmitted and affects sexually active adults and adolescents. The reason for its occurrence in children without evidence of sexual abuse is still unclear. There are several treatment options, but none has been proven to be the most efficacious.
Patients and methods
All patients complaining of GWs were recruited from the Dermatology Outpatient Clinic of Menoufia University Hospital during the period from March to September 2011. The patients were investigated for HIV and syphilis. Cervical Pap smear, colposcopy, and anoscopy were performed. Biopsies were taken from every patient to confirm the diagnosis. Podophyllotoxin 0.5% solution was used for treatment.
Results
A total of 140 cases of GWs were found among patients attending the Dermatology Outpatient Clinic, and included 100 female and 40 male patients (132 adults and eight children). A total of 120 patients received podophyllotoxin treatment and 20 were excluded as they were pregnant. Response to podophyllotoxin was variable and ranged from complete cure to absolute resistance.
Conclusion
Podophyllotoxin was well tolerated and had a good cure rate.

Keywords: Egypt; genital wart; human papillomavirus; podophyllotoxin


How to cite this article:
Attia AM, Bakrey OA, Fakhrey Abd El-Motaleb SM. The use of podophyllotoxin for treatment of genital warts. Menoufia Med J 2015;28:367-71

How to cite this URL:
Attia AM, Bakrey OA, Fakhrey Abd El-Motaleb SM. The use of podophyllotoxin for treatment of genital warts. Menoufia Med J [serial online] 2015 [cited 2019 Dec 7];28:367-71. Available from: http://www.mmj.eg.net/text.asp?2015/28/2/367/163886


  Introduction Top


Human papillomavirus (HPV) infection of the genital tract may be asymptomatic or may manifest as genital warts (GWs), mildly dysplastic lesions, or invasive carcinomas [1] .

GWs constitute the most common sexually transmitted infection (STI), with an estimated annual prevalence of 1% in the sexually active population aged 15-49 years in the USA [2] . However, literature on GWs from North African countries is lacking.

More than 120 different HPV genotypes have been identified and are referred to by number, of which ~40 were detected in the anogenital area [3] .

Multiple therapeutic modalities are used for the treatment of GWs. Most are ineffective, many are painful, and some are dangerous. Podophyllotoxin is the biologically active compound from podophyllin resin. The effect of podophyllotoxin in the treatment of GWs is through its ability to block cell division in metaphase by binding with intracellular tubulin [4] . It may also induce blood vessel damage within warts and may stimulate interleukin production [5] . Although the use of podophyllotoxin has been known for a long time, it became commercially available for therapeutic use in Egypt only recently. There are no studies about its effect in our population.

The aim of this study was to determine the clinical profile of GWs among Egyptians and to evaluate the therapeutic effect of podophyllotoxin.


  Patients and methods Top


All patients attending the Dermatology Outpatient Clinic at Menoufia University Hospital with a complaint of GWs were selected over a period of 6 months; the study population comprised 140 patients of whom 40 were male (including eight children) and 100 were female.

All patients underwent the following:

  1. A genital examination for detection of sites and extent of affection and presence of urethral or vaginal discharge.
  2. Other investigations such as:


    1. Screening for HIV (by ELISA) and syphilis (by venereal disease research laboratory test (VDRL)).
    2. Cervical Papanicolaou (Pap) smear for all female patients and anal Pap smear for patients with perianal lesions.
    3. Colposcopy and anoscopy to search for vaginal/cervical and intra-anal lesions, respectively. Pregnant females were excluded from colposcopic and anoscopic examination.
  3. Pretreatment consent was taken from every patient.
  4. Biopsy specimens (4-6 mm) of the wart lesion were taken from each patient. Each specimen was fixed in 10% neutral buffered formalin, paraffin embedded, and examined by routine pathological analysis.
  5. Podophyllotoxin 0.5% solution was topically applied with a cotton swab twice daily by the patient for 3 consecutive days every week, followed by a 4-day rest period. The surface area treated did not exceed 10 cm 2 , and a maximum of 0.5 ml was used per treatment day. Treatment cycles could be repeated 4-6 times. Pregnant patients were excluded [6] .
  6. Patients were assessed at every visit. Assessment was made by comparing pretreatment and post-treatment images by the authors. Treatment was continued for six cycles after which the case was considered resistant [4] .
  7. The response to treatment was evaluated as follows:


    1. Complete resolution, excellent response 100%.
    2. Partial response, 50-100% reduction in size.
    3. Minimal response, less than 50% reduction in size.
    4. No response.
  8. Once the lesions had completely healed, the patient was followed up for 6 months to detect local recurrence due to HPV latency [4] .


Statistical analysis

Results were collected, tabulated, and statistically analyzed with statistical package SPSS (version 11; SPSS Inc., Chicago, Illinois, USA). Data were statistically described in terms of range, mean ± SD, frequencies (number of cases), and relative frequencies (%) when appropriate. Fisher's exact test and the Mann-Whitney test were used for comparison between different groups. A P value less than 0.05 was considered statistically significant [7] .


  Results Top


This is an open label trial that was carried out during the period from March to September 2011. A total of 140 patients with GWs were recruited from the Dermatology Outpatient Clinic.

Demographic data

Patients included 100 (71.4%) female and 40 (28.6%) male patients with a female to male ratio of 2.5 : 1, and comprised 132 (94.2%) adults and eight (5.8%) children. Among the female patients, 20 (20%) were pregnant. Patients' ages ranged from 9 to 44 years with a mean age of 31.93 ± 9.95 years. The disease duration ranged from 1 to 12 months with a mean duration of 2.16 ± 2.52 months [Table 1].
Table 1 Clinical data of the studied patients

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Clinical data of the studied patients are shown in [Table 1].

Patients presented with papular warts (88 cases, 62.8%) and keratotic warts (52 cases, 37.2%).

Laboratory and endoscopic results

Histopathological examination of hematoxylin and eosin-stained sections confirmed the diagnosis of GWs in all examined cases [Figure 1].
Figure 1: Histopathology of genital warts

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Screening for HIV and syphilis gave negative results in all cases. Cervical Pap smear examination was negative in all examined female patients and anal Pap smear was negative in all cases with perianal warts.

Anoscopic examination in patients with perianal warts and colposcopic examination in nonpregnant women with vulval warts yielded negative results in all examined cases.

Response to podophyllotoxin treatment

Podophyllotoxin was administered in 120 cases. Complete resolution was achieved in 88 (73.3%) cases, partial resolution in eight (6.7%) cases, minimal resolution in eight (6.7%) cases, and no response in 16 (13.3%) [Table 2].
Table 2 Response to podophyllotoxin treatment in studied patients

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The duration of treatment ranged from 2 to 6 weeks [Table 2]. There was a statistically nonsignificant correlation between treatment response and sex (P > 0.05) and between treatment response and disease duration (P > 0.05) [Table 3].
Table 3 Correlation between treatment response and sex, disease duration, and human papillomavirus genotype

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Twenty (16.6%) patients complained of mild irritation and excoriation and 12 (10%) patients complained of erythema and itching. The excluded pregnant women were treated with cryocautery.


  Discussion Top


HPV-associated genital pathology represents one of the major problems in STI clinics, mostly because of the high recurrence rate, difficult eradication, and oncogenic potential [1] .

There has not been specific antiviral and completely satisfactory treatment for GWs so far. Multiple treatment modalities with varying degrees of efficacy are available [4] .

Podophyllotoxin offers a logical evolution and refinement over first-line therapy and replaces the previous use of crude, nonstandardized podophyllin. It is designed for topical self-treatment in 3-day cycles. This regimen is recommended as safe, cost-effective, and convenient for topical therapy [6] .

The aim of this study was to determine the clinical profile of GWs among Egyptians and to evaluate the therapeutic effect of podophyllotoxin.

The selected patients showed a female to male ratio of 2.5: 1. This is in accordance with the results of Gewirtzman et al. [8] and Sturgiss et al. [9] , who stated that the prevalence of the disease is believed to be lower in men than in women. In contrast, Castellsague et al. [10] reported a higher prevalence in males than in females. Longstaff and von Kroghy [4] said that the rate of penile warts may be 6-7%. However, this figure represents only the 'tip of the iceberg', as most people harbor anogenital HPV without showing any symptoms.

Circumcision may be an independent protective factor in men. One study revealed a prevalence of penile HPV colonization of 20% in uncircumcised men, whereas the prevalence in circumcised men was 5.5%. Male circumcision is most effective before sexual debut and presence of the male foreskin facilitates high-risk HPV infection in men and their female partners [11] .

Male circumcision is one of the routine sociocultural and religious habits in our community, which may explain the low prevalence among men in the studied cases. Sexual orientation is another factor that may affect disease prevalence in men. Nyitray et al. [12] stated that the disease is higher in homosexual and bisexual men than in heterosexual ones. All male patients in this study were heterosexual.

The ages of the studied patients ranged from 9 to 44 years. Kahn et al. [13] concluded that the prevalence is highest in women younger than 34 years and then decreases in the 35-44 age group.

Eight male children with perianal warts were detected among the studied patients. The prevalence among children was 52/10 000. Until 1990, only 174 children with GWs had been reported. Nearly 500 additional cases were published by 1998, indicating a rapid increase in awareness of this disease, although one cannot exclude the possibility that the prevalence of GWs in children is truly increasing [14] .

Clinical examination and investigations excluded sexual abuse in the children. Mammas et al. [14] said that children with anogenital warts often give rise to a suspicion of sexual abuse. However, several studies have indicated that the origin of pediatric anogenital HPV infections is unclear. Transmission of HPV in children remains controversial. A child can become infected in utero or during parturition. The prepatent period is difficult to assess, but some clinicians considered an upper limit of 2-3 years from birth. Other routes of infection include sexual abuse and indirect transmission through fomites [15] .

In addition, genital HPV infection is estimated to be subclinical in up to 70% [16] .

A subclinically infected mother may transfer infection that becomes manifest in her child.

Handley et al. [17] followed up 42 prepubertal children with GWs for 15.9 months. Of them, 23.8% had at least one adult family member with GWs, 36.9% had one adult family member with another STI, 62.2% had a mother with cervical intraepithelial neoplasia, and 47.6% had a family member with extragenital warts.

Thus, we can conclude that the presence of GWs in children is not always an evidence of sexual abuse.

There were 20 pregnant women in the survey. HPV infection is not associated with adverse outcomes of pregnancy and the presence of GWs is not an indication for termination of pregnancy. In pregnant women, spontaneous regression of GWs often occurs after delivery. If lesions become large, bleed easily, or cause discomfort, or if the patient chooses, treatment is indicated. Cryotherapy, electrocautery, or the cautious application of trichloroethanoic acid can be used. Laser vaporization yields good results, but when warts are extensive general anesthesia is required [18] . Eassa et al. [19] reported that tuberculin injection is safe and effective for treating pregnant women with GWs.

The appearance of GWs during pregnancy does not necessarily indicate infidelity. Under hormonal influence, HPV is upregulated and, as a result, latent virus, possibly acquired years previously, may become apparent [17] .

Anoscopic and colposcopic examinations of studied cases were negative. Cervical and anal Pap smear was also negative in all examined cases. This is in contrast to the results of Gross et al. [20] who detected cervical lesions in over 50% of women with vulval warts and anal lesions in 8% of men with penile warts.

Approximately 50% of squamous cell carcinomas of outer genitals and of the anal canal are pathogenically related to the persistence and progression of high-risk HPV-induced lesions [21] . Most intraepithelial neoplasia lesions, in as much as 30-40% of females with GWs, disappear without causing harm. About 15% of cervical intraepithelial neoplasia lesions persist and progress to invasive cancer within a time span of about 5-15 years. Thus, the negative Pap smear in any female patient with GWs does not exclude the occurrence of future cervical intraepithelial neoplasia and the test should be repeated especially in a population at risk. The frequency of testing varies from every 3-5 years [22] .

GWs may be associated with other STIs [13] . Screening of cases for concomitant syphilis and HIV was performed and was negative in all cases.

HPV infection occurs when HPV virions access the basal layer of the epithelium and stimulate proliferation of cell division, accompanied by viral replication. To date, there is no pharmacological way to eliminate HPV from human cells. Thus, cell destructive therapies had been the standard of treatment for several decades [23] . Podophyllotoxin was originally only indicated for the treatment of penile warts, with up to 90% clearance rate. Von Krogh [24] proposed that 0.5% podophyllotoxin could be applied by patients twice daily for 3 consecutive days. Since then, a number of clinical studies have evaluated this regimen in both sexes. Clearance rates with podophyllotoxin varied widely, from 45 to 88% [6] . The drug was reported to be safe in children with perianal warts [25] .

Studied patients showed complete resolution in 73.3% of cases, partial resolution in 6.7% of cases, minimal resolution in 6.7% of cases, and no response in 13.3%.

Resistance to treatment may be explained by the fact that keratinocytes surrounding visible lesions may be infected in a latent manner, harboring viral DNA. In case such epithelial cells remain after destructive therapies, they present the source of relapsing infections and stimulate the growth of new lesions. In addition, viral activity may be dormant for several months and cannot be detected by clinical symptoms unless new warts are growing. This results in a high percentage of recurrences [26] .

Stefanaki et al. [1] concluded that the overall clinical cure rates for podophyllotoxin 0.5% solution did not show statistically significant difference from topical imiquimod.

There was a statistically nonsignificant correlation between treatment response and sex and between treatment response and disease duration. These results were similar to previous similar studies [24],[25] . However, the statistically significant correlation between treatment response and HPV genotype had not been discussed before.


  Conclusion Top


From this work we can conclude that podophyllotoxin was well tolerated and had a good cure rate. The drug may provide a cheap therapeutic alternative in poor areas in our country that lack modern facilities for GW treatment.


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Stefanaki C, Hadjivassiliou M, Katzouranis I Bethimoutis G, Nicolaidou E, Anyfantakis V, et al. Prognostic factors for the response to treatment in males with genital warts. J Eur Acad Dermatol Venereol 2009; 23 :1156-1160.  Back to cited text no. 1
    
2.
Partridge JM, Koutsky LA. Genital human papillomavirus infection in men. Lancet Inf 2006; 6 :21-31.  Back to cited text no. 2
    
3.
Donà MG, Palamara G, Di Carlo A. Prevalence, genotype diversity and determinants of anal HPV infection in HIV-uninfected men having sex with men. J Clin Virol 2012; 54 :185-189.  Back to cited text no. 3
    
4.
Longstaff E, von Kroghy G. Condyloma eradication: self-therapy with 0.15-0.5% podophyllotoxin versus 20-25% podophyllin preparations - an integrated safety assessment. Reg Toxicol Pharmacol 2001; 33:117-137.  Back to cited text no. 4
    
5.
Centers for Disease Control and Prevention. Sexually transmitted diseases, treatment guidelines. Morb Mortal Wkly Rep. Atlanta, USA: Department of Health and Human Services; 2002. 51.  Back to cited text no. 5
    
6.
Yan J, Chen SL, Wang HN, Wu TX. Meta-analysis of 5% imiquimod and 0.5% podophyllotoxin in the treatment of condylomata acuminata. Dermatol 2006; 213 :218-223.  Back to cited text no. 6
    
7.
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8.
Gewirtzman A, Bobrick L, Conner K, Tyring SK. In: Gross G, Tyring SK, editors. Epidemiology of sexually transmitted infections. Sexually transmitted infections and sexually transmitted diseases. 3rd ed. Berlin, Heidelberg: Springer-Verlag 2011;312-322.  Back to cited text no. 8
    
9.
Sturgiss EA, Jin F, Martin SJ, Grulich A, Bowden FJ. Prevalence of other sexually transmissible infections in patients with newly diagnosed anogenital warts in a sexual health clinic. Sex Health 2010; 7 :55-59.  Back to cited text no. 9
    
10.
Castellsague X, Bosch FX, Munoz N, Acebes LO, Salinas J, San Martin M. Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners. N Engl J Med 2002; 346 :1105-1112.  Back to cited text no. 10
    
11.
Tobian AA, Gray RH. Male foreskin and oncogenic human papillomavirus infection in men and their female partners. Future Microbiol 2011; 6 :739-745.  Back to cited text no. 11
    
12.
Nyitray AG, da Silva RJ, Baggio ML, Lu B, Smith D, Abrahamsen M, et al. The prevalence of genital HPV and factors associated with oncogenic HPV among men having sex with men and men having sex with women and men: the HIM study. Sex Transm Dis 2011; 38 :932-940.  Back to cited text no. 12
    
13.
Kahn JA, Lan D, Kahn RS. Sociodemographic factors associated with high-risk human papillomavirus infection. Obstet Gynecol 2007; 110 :87-95.  Back to cited text no. 13
    
14.
Mammas IN, Sourvinos G, Spandidos DA. Human papilloma virus (HPV) infection in children and adolescents. Eur J Pediatr 2009; 168 :267-273.  Back to cited text no. 14
    
15.
Jones V, Smith SJ, Omar HA. Nonsexual transmission of anogenital warts in children: a retrospective analysis. Sci World J 2007; 7 :1896-1899.  Back to cited text no. 15
    
16.
Syrjanen K, Syrjanen S. Papillomavirus infections in human disease. 3rd ed. New York: J. Wiley & Sons 2000; 1-615.  Back to cited text no. 16
    
17.
Handley J, Dinsmore W, Maw R. Anogenital warts in prepubertal children; sexual abuse or not? Int J STD AIDS 1993; 4 :271.  Back to cited text no. 17
    
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McMillan A. Sexually transmissible infections in clinical practice. 2nd ed. London: Springer-Verlag Ltd 2009; 191.  Back to cited text no. 18
    
19.
Eassa BI, Abou-Bakr AA, El-Khalawany MA. Intradermal injection of PPD as a novel approach of immunotherapy in anogenital warts in pregnant women. Dermatol Ther 2011; 24 :137-143.  Back to cited text no. 19
    
20.
Gross G, Ikenberg H, Gissmann L, Hagedorn M. Papillomavirus infection of the anogenital region: correlation between histology, clinical picture, and virus type. Proposal of a new nomenclature. J Invest Dermatol 1985; 85 :147-152.  Back to cited text no. 20
    
21.
Melbye M, Frisch M. The role of human papilloma viruses in anogenital cancers. Semin Cancer Biol 1998; 8 :307-313.  Back to cited text no. 21
    
22.
Saslow D, Solomon D, Lawson HW. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology Screening Guidelines for the Prevention and Early Detection of Cervical Cancer. J Lower Genit Tract Dis 2012; 16:1-29.  Back to cited text no. 22
    
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Hebner CM, Laimins LA. Human papilloma viruses: basic mechanisms of pathogenesis and oncogenicity. Rev Med Virol 2006; 16 :83-97.  Back to cited text no. 23
    
24.
Von Krogh G. Podophyllotoxin for condylomata acuminata eradication. Clinical and experimental comparative studies on Podophyllum lignans, colchicine and 5-fluorouracil: hesis. Acta Dermatovenereol Suppl 1981; 98 :1-48.  Back to cited text no. 24
    
25.
Strand A, Brinkeborn RM, Siboulet A. Topical treatment of genital warts in men, an open study of podophyllotoxin cream compared with solution. Genitourin Med 1995; 71 :387-390.  Back to cited text no. 25
    
26.
Claesson U, Lassus A, Happonen H, Hogstr¨om L, Siboulet A. Topical treatment of venereal warts: a comparative open study of podophyllotoxin cream versus solution. Int J STD AIDS 1996; 7 :429-734.  Back to cited text no. 26
    


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