|With its implications of sexual transmission and potential cervical cancer, a diagnosis of genital warts can be emotionally distressing to patients. Because no single treatment serves every patient, the best approach to selecting a therapeutic option considers the extent of the disease, wart location, and the patient's individual needs.
Jonathan B. Parmer, MD*, Eugene J. Basiliere, MD*, Elaine K. Orenberg, PhD*
Patients' concerns about genital warts (condylomata acuminata) generally reflect the current state of ignorance, half-knowledge, and fear about the disease and the virus that causes it. Patients who present after numerous failed treatments want to know whether the warts will ever be eradicated, whether they are now at increased risk of cervical cancer, and whether their fertility or future pregnancies will be affected. Some will be angry at the partner who infected them or apprehensive about the risk to their partner, while others may be too devastated at the diagnosis of a sexually transmitted disease (STD) to discuss the topic. Patients who are fearful and upset are often less compliant with a treatment regimen, exacerbating the problem.
The best approach to managing genital infection caused by human papillomavirus (HPV) is to win the patient's trust and confidence so that she can work in partnership with the physician. Genital warts, while posing a lower morbidity risk than other STDs, are nonetheless frustrating in that no one treatment suits every patient, every physician, or every occurrence or recurrence of the disease.
The numerous therapeutic modalities available fall into two general categories: those the patient applies and those the physician administers. While many studies have been conducted on these modalities, their relative efficacy defies objective assessment. Controlled, comparative studies are rare, and study designs vary as to the number, location, and size of the warts and patient selection. For these reasons, and also because patient numbers are often small, retrospective comparative studies are difficult to perform. In addition, continuity of follow-up is often problematic. Several new lines of treatment are being explored more systematically, however; for example, an immune-response modifier that the patient applies has recently appeared on the market. Furthermore, a recent series of prospective studies has objectively evaluated an innovative intralesional treatment.
Genital HPV infection--the most common viral STD in the United States--has reached epidemic proportions among Americans of all age groups. Because it is not a reportable disease, its precise prevalence is unknown. however, HPV has been estimated to affect more than 10 million people in this country.1-4 More than 2% of the sexually active population is thought to have visible genital warts, which represent only the tip of the iceberg; up to 4% of this population may have subclinical infection, while 14% may have latent infection with HPV DNA but no clinical signs. nearly 100 million men and women are at risk for acquiring HPV infection.3 Moreover, the number of patients with the infection is increasing.1
The association between cervical cancer and HPV DNA is especially worrisome. While the most common sources of genital warts--HPV types 6 and 11--are rarely associated with malignancy,5 the high-risk HPV types 16 and 18 have been found in more than 90% of cervical cancers.6 Cofactors such as smoking, poor diet, oral contraceptive use, immune compromise, and a history of multiple sexual partners or STDs may also play a part.4,7
The management of genital warts in the pregnant patient presents an additional problem: the relative immune suppression of pregnancy may lead to accelerated growth,8 even to the obstruction of the birth canal.9 In general, beyond the cosmetic and psychological burden to the patient, genital warts can cause significant morbidity. Some grow large enough to impair sexual functioning, and lesions may itch, burn, or ache.5,10 Very large warts can become infected from repeated trauma.11
Prevention is problematic as well. HPV is transmitted by direct skin-to-skin contact, rather than by exchange of body fluids, rendering condoms less effective than with other STDs. However, those having sex with new partners should use condoms. Condoms that cover the affected area may reduce transmission risk, but transmission may still occur after contact with areas not covered by the condom including skin with visible warts or latent disease. Studies show that most sexual partners of patients diagnosed with genital warts are also infected. The virus is remarkably persistent despite therapy and wart recurrences are almost certainly due to subclinical infection in the patient and not reinfection from the partner.11 Therefore, patients in a stable, monogamous relationship are often advised that condoms are not necessary.10
Genital warts, which are usually transmitted by physical contact during sexual activity, are highly
contagious. While they appear an average of 3 months after exposure,8,12 the latency period can be much longer. Once present, they remain unchanged in size, spontaneously regress, or spread.8,13 Because the warts have no known cure, treatment goals are to rid the patient of visible lesions and reduce symptoms.7,13 Even with initially successful treatment, the recurrence rate is high.
Infection can be clinically apparent, subclinical, or latent. Clinically visible warts are usually flesh-colored or pale pink, with many discrete projections on a wide base. When numerous and large, they may coalesce into plaques.5,14 In women, most warts are located posteriorly at the introitus--probably because the virus is attracted to genital areas that undergo slight trauma during sexual activity. The prevalence is smaller on the labia and clitoris, and even less on the perineum, vagina, anus, and cervix.8,10
|Table 1. Differential Diagnosis of Genital Warts|
|Common benign skin lesions|
|Micropapillomatosis labialis||On epithelium of labia minora; each projection has own base; most patients have had recurrent candidiasis, trichomoniasis, or chlamydia, but are otherwise asymptomatic|
|Seborrheic keratoses||Hypertrophic lesions with rough surfaces|
|Nevus||Raised or pedunculated|
|Condyloma lata (secondary syphilis)||Broad-based, smooth-surfaced lesions|
|Herpes simplex virus||Vesicular eruption with red base and ulcerations|
|Molluscum contagiosum||Umbilicated yellowish papules with central core|
|Neoplasms (perform biopsy if suspected)|
|iant condyloma or Buschke-Lowenstein tumor||Sessile, confluent, cauliflower-like mass of warts locally invasive|
|Bowenoid papulosis||Rough papules 2 mm-4 mm in diameter, flesh-colored to reddish-brown, resists therapies|
|Squamous cell carcinoma||Red, firm nodule gradually forming a shallow ulcer surrounded by an indurated border|
|Malignant melanoma||Pigmented, flat, or raised with variable color or shape|
Diagnosis of genital warts is usually made by physical examination. It is important to distinguish genital warts from other genital lesions (Table 1). As each STD requires specific treatment, biopsy should be considered for lesions that are not typically acuminate or that do not respond as expected to treatment because they may be neoplasms.
Subclinical infections may be detected by applying 3% to 5% acetic acid solution for 5 to 10 minutes. The lesions then become visible, and can be further visualized via colposcopy. Histologic testing can verify the presence of clinical and subclinical infection, but cannot determine the viral type in terms of risk for cervical intraepithelial neoplasia or cervical cancer. HPV cannot be cultured, and serologic tests are not available to test for HPV antibodies. DNA hybrid capture can determine the viral subtype or infer a latent infection--ie, presence of HPV DNA in clinical and histologically "normal" skin. Subclinical or latent infection may account for the high recurrence rate by acting as a reservoir for subsequent reinfection.11
Because many patients are discouraged to learn that viral eradication is not currently possible, it is all the more important to educate them that treatment can alleviate and sometimes even eliminate the clinical disease. Relieving the physical discomfort and the cosmetic burden can help patients redefine their disease as one they can manage. Promoting the realistic goal of eliminating visible warts and prolonging the wart-free period will not only improve the patient's physical well-being, but also assuage many of her anxieties and concerns.7,11,13
For example, patients worried about contagion may be relieved to learn that removing the visible warts may reduce the viral burden and thereby the risk of transmission.11,13 Patients with cancer fears may be especially receptive to teaching. Emphasizing the importance of periodic check-ups can contribute to their overall health, and make them more vigilant about follow-up. These patients may also be more cooperative in presenting for regular Papanicolaou smears, which are the best preventive procedure for cervical cancer.7 Cervical cytology can identify
cellular changes (eg, koilocytosis) associated with HPV.15 Further tests for HPV can verify whether the histologic changes are associated with the presence of low- or high-risk HPV subtypes.
Other patients may have fears related to pregnancy. Genital warts may increase in size during pregnancy,8 complicating delivery and posing a risk of laryngeal papillomatosis in neonates delivered vaginally.8,16,17
The role of cesarean delivery is unclear in preventing laryngeal papillomatosis,16,17 so pregnant patients and those planning pregnancies should be encouraged to undergo treatment. While genital warts per se do not impair fertility, treatments for cervical dysplasia may do so--arguing for early treatment and strict follow-up.
Patients need to know that although some genital warts regress spontaneously, the likelihood of regression is unpredictable. By adopting a "wait-and-see" attitude, they may find that the warts instead increase in size and number, making treatment more difficult and expensive.10
Many patients feel guilty about the diagnosis of an STD. Putting the disease into perspective may help: an HPV infection need be no more occasion for guilt than a rhinovirus infection. And for patients who are distressed at the appearance of warts in the context of a long-term, monogamous relationship, it may help to know that recurrences due to auto-reinfection can appear even years after the initial infection. Enlisting the patient's cooperation confers mutual benefits, with the patient gaining a sense of control and enhanced emotional well-being and the physician improving the likelihood of a favorable outcome by promoting patient compliance.
|Table 2. Options for Treatment of Genital Warts|
|Trichloroacetic acid (TCA)|
|CO2 laser ablation|
|Loop electrosurgical excisional procedure|
|Fluorouracil/epinephrine injectable gel|
Several chemical agents lend themselves to self-administration by the patient. Physician-administered modalities generally fall into chemical and ablative types, with the recent addition of intralesional therapy. The existence of a host of treatment approaches--each with highly disparate efficacy rates, even within a single treatment type
--illustrates the essential problem: all treatments have limitations, and no single approach is ideal. Further limitations are a lack of rigorous, placebo-controlled trials--a situation that is changing with recent prospective trials performed on interferons, imiquimod, and intralesional fluorouracil/epinephrine injectable gel.
Patients may demand certain treatments based on research or hearsay, but it is the physician's responsibility to explain that therapy must be individualized for each patient and may depend on the clinical course (eg, new onset or recurrence). Other considerations are the anatomic location of the warts and severity of the disease. Some patients may be unable to comply with self-applied regimens--even those that are apparently easy to use. Treatments that are initially low in cost can become expensive if retreatment is required.10,18 Options such as laser treatment may be too expensive or unavailable except in large centers. Other therapies may result in intolerable adverse effects.
The clearance and recurrence rates given here are not strictly comparable because they are variously reported as per-patient and per-wart response rates. In addition, dissimilar study designs, reports from single studies, and studies that are not prospectively designed point to therapeutic limitations as well as to limitations within the medical literature. Table 2 lists common treatment options for genital warts.
Podophyllin--a natural, plant-based resin of variable potency that has long been a mainstay in the treatment of genital warts--is often chosen as the first line of treatment. Until recently, however, podophyllin could only be applied by the physician and caused considerable discomfort. Podofilox cream is a purified form of podophyllin with standard potency that can be self-applied and need not be washed off. The package insert reports a 50% per-patient response rate and a 79% per-wart response rate, with recurrence rates of 60% and 35%, respectively. Side effects are similar to those experienced with podophyllin, but milder. Treatment is twice daily for 3 days followed by 4 treatment-free days for up to 4 weeks. Podofilox is also available as a gel, but response rates are lower.7,18,19
Although its use is limited, topical fluorouracil cream has been employed successfully to treat warts of the urinary meatus in men20 and vaginal warts in women and to prevent recurrence of vaginal and vulvar warts postablation.21 The preparation should be used cautiously for vaginal warts because of its high complication rate, including pain, watery discharge, and denuding of vaginal epithelium.10,19 Success and recurrence rates average 71% and 13%, respectively, based mostly on studies of vaginal or penile/urethral treatment.19 To treat vulvar and perianal warts, the cream is applied once or twice weekly at bedtime for up to 10 weeks, and must be washed off in the morning. Its use is contraindicated during pregnancy.
Imiquimod, a recently approved immune-response modifier supplied in a cream base, is self-applied three times weekly for up to 16 weeks.22 In a clinical trial in which 109 patients were treated with active drug, the overall response rate (more than half of wart area cleared) was 76% for men and women combined; the complete response rate was 50%.22 Imiquimod should be washed off after 6 to 10 hours. Sexual contact should be avoided while the cream is on the skin, and the compound can weaken condoms and diaphragms.
Physician-applied podophyllin preparations are relatively inexpensive and convenient, and have efficacy rates ranging from 22% to 100% in clinical trials.7,18,19 Best used for small external warts, podophyllin is unsuitable for vaginal or cervical warts and is contraindicated during pregnancy.5,13 Physician-applied podophyllin should be washed off after 12 hours. Local reactions can include erosion, ulcerations, scarring, pain, itching, tenderness, and irritation. Recurrence rates can be as high as 74%.7
Trichloroacetic acid (TCA) is another option that is safe for use during pregnancy,5 effective for external warts, and cost-effective. Because its depth of penetration can be difficult to control, TCA requires careful application. Scarring and ulceration can occur. TCA is more painful than podophyllin or podofilox, and causes similar damage to normal tissue. Efficacy data are limited. In one study, the response rate was 81%, with a recurrence rate of 36%; in another, response with TCA plus podophyllin was no better than with podophyllin alone.7,19
Cryotherapy is safe during pregnancy, but is typically limited to small warts and requires several office visits. Adverse events--eg, transient local pain or burning, ulceration that resolves within a week to 10 days without scarring--are fairly well-tolerated by patients.7,15 For many physicians, cryotherapy represents the simplest and least painful ablative option for external warts. Efficacy rates range from 63% to 88%, with recurrence rates of 21% to 39%.7
CO2 laser ablation precisely destroys wart tissue, and is often used when other modalities have failed. It is one of the preferred options for treating vaginal warts.10 Because of the training, equipment, and hospitalization required, this method is relatively expensive. Clearance rates of 31% to 94% have been reported, while recurrences range between 3% and 95%.7 The chief risk is thermal damage to normal tissue, but pain, vaginal discharge, itching, swelling, and scarring may also occur.7,16,23 This treatment method may pose a high risk to physicians, nurses, and patients because laser smoke plumes can carry viral particles.19 Thus, good smoke evacuation methods and masks are essential during treatment.
The loop electrosurgical excisional procedure (LEEP) has a success rate of 90%, is fairly easy to learn, and is increasing in popularity. It can also be used to treat vaginal warts and its efficacy is comparable to that of laser surgery, but it is more cost-effective. The main complication is bleeding. Because HPV particles could be present in the LEEP smoke plume, the same precautions should be taken as with laser surgery.19 Other electrosurgical procedures have similar efficacy rates, with recurrence rates in the range of 22% to 24%.7,19
Standard surgery has been reported to have a success rate of 93%, with recurrence rates in the range of 24% to 29%.7,19 It requires local anesthetic, and is limited mainly to treatment of perianal warts. Scarring can be a complication.16
Intralesional treatment--first explored using interferons--overcomes the problem of absorption of chemical therapeutic agents, especially through heavily keratinized warts. The treatment dose for interferon is 1 million units per wart, two to three times weekly for up to 8 weeks.19 Some authors suggest combination treatment with interferons and topical podophyllin.24,25 Response rates for a-interferon (both recombinant and human leukocyte-derived) range from 42% to 54%, with recurrence rates of 19% to 24%7,19. Flu-like symptoms lasting 6 to 8 hours after the injection are the most common adverse reaction. Reversible leukopenia and elevated levels of liver enzymes may occur after 3 weeks of use.19
Simple solutions of drugs injected locally can be cleared from the affected site so rapidly that many of the potential advantages of intralesional administration are lost. By contrast, intralesional chemotherapy using fluorouracil/epinephrine injectable gel (5-FU/epi gel) delivers the cytotoxic drug (fluorouracil) in a viscous aqueous gel with epinephrine. This formulation provides high local drug concentrations and continued bioavailability at the injection site without systemic toxicity. In a study of 348 male and female patients with external warts of all sizes and varying locations, a regimen of six injections at weekly intervals over an 8-week period yielded an overall wart response rate (more than half of wart area cleared) of 87% and a complete response rate of 78%.26 The recurrence rate was 43% within the 3-month follow-up period.26
This treatment modality may benefit physicians and patients encountering recurrent or recalcitrant warts.1 For these patients, the complete response rate (all warts cleared) was as good as or better than for those who had never been treated. Intralesional 5-FU/epi gel may also be useful for patients who find it difficult to comply with self-applied treatments or who prefer physician-directed therapy.
Physicians must arrive at their own preferences from among the broad range of treatments offered for genital warts. The choice depends on the specific needs of the patient--physical, emotional, and financial--and on the treatment modalities most readily available in a given area. Ultimately, however, selection is determined by the ongoing partnership that physician and patient develop together as a means of coping with this multifaceted disease.
1. Division of STD Prevention, US Department of Health and Human Services. Sexually transmitted Diseases Surveillance 1995. Public Health Service, Centers for Disease Control and Prevention, Atlanta, GA, 1995.
2. Committee on Prevention and Control of Sexually Transmitted Diseases. Eng TR, Butler WT, eds. The Hidden Epidemic: Confronting Sexually Transmitted Diseases. Washington, DC: National Academy Press; 1997.
3. Koutsky LA, Galloway DA, Holmes KK. Epidemiology of genital human papillomavirus infection. Epidemiol Rev. 1988;10:122-163.
4. Franco ELF. Epidemiology of anogenital warts and cancer. Obstet Gynecol Clin North Am. 1996;23:597-623.
5. Reid R. The management of genital condylomas, intraepithelial neoplasia, and vulvodynia. Obstet Gynecol Clin North Am. 1996;23:917-991.
6. Bosch FX, Manos MM, Mu–oz N, et al. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. J Natl Cancer Inst. 1995;87:796-802.
7. Kraus SJ, Stone KM. Management of genital infection caused by human papillomavirus. Rev Infect Dis. 1990;12(suppl 6):620S-632S.
8. Oriel JD. Natural history of genital warts. Br J Vener Dis. 1971;47:1-13.
9. Osborne NG, Adelson MD. Herpes simplex and human papillomavirus genital infections: controversies around obstetric management. Clin Obstet Gynecol. 1990;33:801-811.
10. Ferenczy A. Epidemiology and clinical pathophysiology of condylomata acuminata. Am J Obstet Gynecol. 1995;172:1331-1339.
11. Ling MR. Therapy of genital human papillomavirus infections. Part I: Indications for and justification of therapy. Int J Dermatol. 1992;31:682-686.
12. Stone KM. Human papillomavirus infection and genital warts: update on epidemiology and treatment. Clin Infect Dis. 1995;20(suppl 1):91S-97S.
13. Centers for Disease Control and Prevention. Sexually transmitted disease treatment guidelines. MMWR. 1993;42:83-88.
14. Greene I. Therapy for genital warts. Dermatol Clin. 1992;10:253-266.
15. American College of Obstetricians and Gynecologists. Genital human papillomavirus infections. ACOG Technical Bulletin. No. 193, June 1994.
16. Bonnez W, Reichman RC. Papillomaviruses. In: Mandell GL, Bennet JE, Dolin R, eds. Principles and Practice of Infectious Diseases. New York: Churchill Livingstone; 1995;1387-1400.
17. Kashima HK, Mounts P, Shah K. Recurrent respiratory papillomatosis. Obstet Gynecol Clin North Am. 1996;23:699-706.
18. Strauss MJ, Khanna V, Koenig JD, et al. The cost of treating of genital warts. Int J Dermatol. 1996;35:340-348.
19. Mayeaux EJ, Harper MB, Barksdale W, Pope JB. Noncervical human papillomavirus genital infections. Am Fam Physician. 1995;52(1):1137-1146.
20. Dretler SP, Klein LA. The eradication of intraurethral condyloma acuminata with 5 per cent 5-fluorouracil cream. J Urol. 1977;113:195-198.
21. Krebs H-B. Treatment of genital condylomata with topical 5-fluorouracil. Dermatol Clin. 1991;9:333-341.
22. Data on file for ALDARA (imiquimod). 3M Pharmaceuticals, St. Paul, Minn.
23. Brown DR, Fife KH. Human papillomavirus infections of the genital tract. Med Clin North Am. 1990;74;1455-1485.
24. Hatch K. Clinical appearance and treatment strategies for human papillomavirus: a gynecological perspective. Am J Obstet Gynecol. 1995;172(suppl pt. 2):1340-1344.
25. Douglas JM Jr, Eron LJ, Judson FN, et al. A randomized trial of combination therapy with intralesional interferon a2b and podophyllin versus podophyllin alone for the therapy of anogenital warts. J Infect Dis. 1990;162:52-59.
26. Swinehart JM, Sperling M, Phillips S, et al. Intralesional fluorouracil/epinephrine injectable gel for treatment of condylomata acuminata. Arch Dermatol. 1997;133:67-73.
Jonathan B. Parmer, MD, is a Clinical Assistant Professor of Gynecology and Obstetrics at Stanford University School of Medicine in Stanford, California. Eugene J. Basiliere, MD, is Chief of the Department of Obstetrics and Gynecology at Sharp Chula Vista Medical Center in Chula Vista, California. Elaine K. Orenberg, PhD, is Director of Professional Services at Matrix Pharmaceutical, Inc., in Fremont, California.
*The "Conflict-of-Interest Policy" of the College of Medicine requires that faculty participating in a CME activity disclose to the audience any relatioship with a pharmaceutical or equipment company which might pose a potential, apparent or real conflict of interest with regard to their contribution to the program. Drs Parmer and Basiliere report no conflict of interest. Orenberg is an employee of Matrix Pharmaceutical, Inc.
Originally published in The Female Patient -- December, 1997
© Copyright, 1997 Quadrant Publishing, All Rights Reserved
Reprints are not allowed without the expressed written consent of Quadrent Publishing.