Also known as condylomata acuminata or venereal warts, is one of the most common types of sexually transmitted infection and primarily affect younger people.

The disease usually is caused by HPV genotypes 6 or 11, which normally are not involved with cancers but can cause abnormal pap smear.

In 8 to 14%, the person has been infected with more than one type of HPV

Genital Warts

50 to 80 percent of sexually active women are infected at least once in their lifetime.

Transient or undetectable

Women under 25 to 30 years have higher rates of infection although a second peak has been described in postmenopausal women.

Association with HPV genotypes 16 and 18 can give rise to subclinical lesions associated with CIN and squamous cancer.

Approximately 1 million cases of genital warts occur each year in the United States and an estimated 32 million cases occur worldwide.

In women, genital warts can appear on the vulva, the walls of the vagina, the perianal area, and the cervix. May increase in size during pregnancy.

In men, they may be found on the tip or

shaft of the penis, the scrotum, or the anus.

In neonates, respiratory & laryngeal papillomatosis follows NVD but can occur after C/S. Typically presents between 2 & 3 years of age and extends into adolescence.

About 37% of laryngeal papillomatosis become malignant.

Occurs more commonly in first-born children and in the children of young mothers who had genital warts.

100 types of HPV ( double stranded DNA virus)

Viral replication takes place only in fully differentiated epithelium.

Cutaneous and mucosal types, High, intermediate and low risk types

Papule or plaque

can also remain dormant within epithelial cells without visible disease

HPV type 2 on hands and feet

Biology

Benign lesion: the viral genome replicates separately to the host cell’s DNA.

Malignant lesion: the HPV DNA is integrated into the host cell’s chromosomes.

After integration a series of events leads to deregulation of the E6 and E7 genes of HPV.

5 - Fluoruracil (5-Fu) Antimetabolic Bichloroacetic or Trichloroacetic Acid Tissue Chemical Destruction

Cryotherapy Physical Freezing Surgical Excision or Curettage Surgical Removal Cautery Tissue Physical Destruction Imiquimod Immunomodulator Interferon Antiviral(immunomodulator) CO2 Laser Tissue Vaporization Podophyllin Antimitotic Podophyllotoxin Antimitotic Vacinne Antiviral(immunomodulator)

Summary of the mechanisms of action of the used drugs for genital warts DRUG MECHANISM OF ACTION

5-FU for genital warts in non-immunocompromised

individuals ( Intervention Review)Claudio S Batista, Álvaro N Atallah,

HumbertoSaconato, Edina MK da Silva2010 The Cochrane Collaboration.

Published by John Wiley & Sons, Ltd.

Types of studies, Only randomized controlled trials (RCTs) were included in this review

Types of participants, Women and men aged 18 years or more, nonimmunocompromised, with clinical or subclinical genital warts.

Methods

5-FU Vs placebo 5-FU 5% Vs Meta-cresol-sulfonic Acid (MCSA) 5-FU 5% Vs Podophyllin 5-Fu 5% Vs CO2 Laser 5-FU 5% Vs 5-FU 5% + INF -2a (Low dose) 5-FU 5% Vs 5-Fu 5% + INF -2a (High dose) 5- FU 5% Vs 5-FU 5% + CO2 Laser + INF -2a

(High dose) 5-FU 5% + CO2 Laser Vs CO2 Laser plus

Types of interventions

Primary Outcomes • Patient or warts response: cure or partial

improvement • Recurrence rate

Secondary Outcomes • Local reactions • Other related adverse events (alteration in

lab data)

Types of outcome measures

Botacini et al, 1993,5% vag. gel 5 gr Qod x15

Females with HPV infection 64 Vs 16 The outcomes after 12 wks Rx were: Cure(-ve colpo, pap & Bx): 52/64 vs 5/16 *

0.02 Partial response (only+ve cyto): 7/64 vs 1/16 No response: 5/64 vs 10/16 *

1. 5-FU Vs placebo

Syed at al, 2000, 1% vag. gel 4 gr Qod x4 wks 30 females in each group with intravaginal warts 312 genital warts: 162 Vs 150 The results were: Cure (Nl colpo & -ve HPV): 25/30 Vs 4/30 * 0.02 side effects : 2/30 Vs 1/30 Lesion recurrence : 2/30 Vs 1/30 Warts cure:141/162 lesions Vs 21/150 * 0.0001 Low index of side effects ( local Rxn, dysuria & local

hypersensitivity )

1. 5-FU Vs placebo

Weissmann et al, 1982, 0.5% gel. Anogenital warts

59 patients: 30 male (14 Vs 16) & 29 female (16 Vs 13 )

The results were: Cure: 18/30 patients (10/14 male & 8/16 female) Vs

8/29 patients (4/16 male & 4/13 female) * 0.031 Improvement: 6/30 patients (2/14 male & 4/16 female)

Vs 4/29 patients, (1/16 male & 3/13 female), No response: 6/30 patients (4/14 male & 2/16 female)

Vs 17/29 patients (8/16 male & 9/13 female). * 0.0068

1. 5-FU Vs placebo

Data from these 3 studies Botacini 1993; Syed 2000; Weismann 1982 could be pooled but demonstrated heterogeneity (I 2= 62%).

[RR 0.39 (95% CI, 0.23 -0.67)]. NNT = 2

Meta-analysis

Botacini et al, 1993, all females 74 patients Vs 9 (MCSA Qod x30 days) Results after 12 weeks were: Cure: 52/74 Vs 3/9 * Partial response: 7/74 patients Vs 1/9 No response: 15/74 patients Vs 5/9 *

0.0075

2. 5-FU 5% Vs Meta-cresol-sulfonic Acid (MCSA)

Botacini et al, 1993, all females 74 pts 5-FU 5% gel (2/wk x8 wks), 40 pts Podophyllin 2% (vag.gel 5gr Qod x15) 5 pts Podophyllin 4%. (vag. gel 5gr Qodx15) The results after 12 weeks: Cure: 52 patients /19/ 3 * Partial response: 7 patients/5/1 No response: 15 patients/16/1 * 0.039

3. 5-FU 5% Vs Podophyllin 2% & 4%

Wallin et al, 1977, All males 42 male patients:20 patients(cream qhs x2w) Vs

22 ( solution by doctor weekly x 4) Withdrawals: 2 Vs 3 The results after 4 and 9 weeks. Cure after 4 weeks : 10/18 patients Vs 11/19 0.89 Cure after 9 weeks: 6/18 patients Vs 10/19 Recurrence of lesions p less than 0.00001

3. 5-FU 5% Vs Podophyllin 25%

Data from two studies (Botacini 1993; Wallin 1977) could be pooled and did not demonstrate heterogeneity (I2 = 32%).

[RR 1.26 (95% CI, 0.86 - 1.82)]. NNT = 6

Meta-analysis

Relakis, 1996, performed 3 study groups all males Condyloma Acuminatum (CA): cream qhsx5, if no response

other 3 courses, Condyloma Plain (CP): single dose Condyloma acuminatum & plain (CA+CP): single dose

The only studied outcome was Treatment Failure.

Lesion Recurrence observed in the first year after treatment was considered as Treatment Failure

Side Effects were observed in 11% of the patients treated with 5-FU

4. 5-FU 5% Vs CO2 Laser

In CA group, 33 males Vs 12 Treatment Failure was: 8/33 Vs 4/12 0.53 In CP Group, 156 males Vs 39 Results were: 29/156 Vs 12/39 0.085 In CA + CP Group, 29 males Vs 20 Results were: 14/29 Vs 14/20 0.12

4. 5-FU 5% Vs CO2 Laser

Relakis et al, 1996, all male patients 5FU 2 courses x 5 days + INF 1.5 SC x 6

days In CA group: 33 Vs 27 Results were 8/33 Vs 7/27 0.88 In CP group: 156 Vs 18 Results: 29/156 Vs 2/18 0.34 In CA + CP Group: 29 patients Vs 0 Results 14 patients

5. 5-FU 5% Vs 5-FU 5% + INF-2a (Low Dose)

Relakis et al, 1996, all males 5FU 5% cream 2 courses x 5days + INF 3 IU

SC x 6 days In CA Group: 33 Vs 0 Treatment Failure in 8/33 In CP Group: 156 patients Vs 58 Result: 29/156 Vs 1/58 In Ca + CP Group : 29 Vs 0 Result: 14/29 patients

6. 5-FU 5% Vs 5-FU 5% + INF-2a (High dose)

Relakis et al., 1996, All males CO2 laser after 2 courses of 5FU cream In CA group: 33 Vs 30. Results: 8/33 patients Vs 0/30 0.056 In CP group: 156 Vs 20 Results: 29/156 Vs 1/20 0.18 In CA + CP group: 29 Vs 16 Results: 14/29 patients Vs 3/16 Treatment failure * 0.00001

7. 5-FU 5% Vs 5-FU 5% + Laser CO2+ INF-2a (High dose)

Carpinello et al., 1988, all males 5FU 5% one wk after Laser x 30 days 68 patients, 41 Vs 27 The outcome studied was Lesion Recurrence Even one lesion after treatment Results: 28/41 Vs 19/27 0.86

8. CO2 Laser Vs CO2 Laser + 5 FU 5%

Considering cure alone, 5-FU was superior to placebo, to MCSA and the Podophylin considering only treatment failure/ no

response, 5-FU was superior to placebo, to MCSA, Podophylin 2% and equal to CO2 Laser and 5FU + INF-2a (low dose) and inferior to 5-FU + INF - 2a ( high dose) and 5FU + Co2 Laser +INF- 2a (high dose).

Conclusion

There was no statistical significance between the treatments of 5-FU + INF - 2a (high dose) and 5-FU + Laser of Co2 + INF- 2a (high dose).

5-FU is a good treatment option in view of the costs of INF- 2a and the CO2 Laser.

Conclusion

Six trials involving 988 pts (645 women and 343 men) and reporting 8 comparisons were evaluated.

Two studies reported withdrawals and dropouts.

5-FU presented better results for cure than placebo or no treatment (relative risk RR 0.39), meta-cresol-sulfonic acid (MCSA) (RR 2.11, 95% ), Podophyllin 2%, 4% or 25% (RR 1.26, 95% CI 0.86 to 1.82).

Main results

There were no statistical differences for treatment failure for 5-FU Vs CO2 Laser (RR 0.69, 95% CI 0.43 to 1.11) Vs 5-FU + INF-2a (low dose) (RR 1.02, 95% CI 0.87 to 1.119).

Worse results were found for 5-FU Vs 5-FU + INF-2a (high dose) (RR 10.78, 95% CI 1.50 to 77.36), and 5-FU + CO2 Laser + INF-2a (high dose) (RR 7.97, 95% CI 2.87 to 22.13).

Main results

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