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.

 	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.

 Moreover, the number of patients with the infection is increasing.

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,

 the 	high-risk HPV types 16 and 18 have been found in more than 90% of cervical cancers.

 	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.

The management of genital warts in the pregnant patient presents an additional problem: the relative immune 	suppression of pregnancy may lead to accelerated growth,

 even to the obstruction 	of the birth canal.

 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.

 Very large warts can become infected 	from repeated trauma.

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.

 Therefore, patients in a stable, monogamous 	relationship are often advised that condoms are not necessary.

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,

 the latency period can be much 	longer. Once present, they remain unchanged in size, spontaneously regress, or spread.

 Because the 	warts have no known cure, treatment goals are to rid the patient of visible lesions and reduce symptoms.

 	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.

 	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.

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.

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.

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.

 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.

 Cervical cytology can identify 
 	cellular changes (eg, koilocytosis) associated with HPV.

 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,

 complicating delivery and posing a risk of laryngeal papillomatosis in neonates delivered 	vaginally.

The role of cesarean delivery is unclear in preventing laryngeal papillomatosis,

 	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.

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.

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.

 	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.

Although its use is limited, topical fluorouracil cream has been employed successfully to treat warts of the 	urinary meatus in men

 and vaginal warts in women and to prevent recurrence of 	vaginal and vulvar warts postablation.

 The preparation should be used cautiously 	for vaginal warts because of its high complication rate, including pain, watery discharge, and denuding of vaginal 	epithelium.

 Success and recurrence rates average 71% and 13%, respectively, 	based mostly on studies of vaginal or penile/urethral treatment.

 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.

 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%.

 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-administered Modalities 
 	Chemical preparations

Physician-applied podophyllin preparations are relatively inexpensive and convenient, and have efficacy rates 	ranging from 22% to 100% in clinical trials.

 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%.

Trichloroacetic acid (TCA) is another option that is safe for use during pregnancy,

 	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.

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.

 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%.

 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.

 	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%.

 	The chief risk is thermal damage to normal tissue, but pain, vaginal discharge, itching, swelling, and scarring 	may also occur.

 This treatment method may pose a high risk to physicians, 	nurses, and patients because laser smoke plumes can carry viral particles.

 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.

 	Other electrosurgical procedures have similar efficacy rates, with recurrence rates in the range of 22% to 24%.

Standard surgery has been reported to have a success rate of 93%, with recurrence rates in the range of 24% 	to 29%.

 It requires local anesthetic, and is limited mainly to treatment of 	perianal warts. Scarring can be a complication.

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.

 Some authors suggest combination 	treatment with interferons and topical podophyllin.

 Response rates for a-interferon 	(both recombinant and human leukocyte-derived) range from 42% to 54%, with recurrence rates of 19% to 24%

. 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.

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%.

 	The recurrence rate was 43% within the 3-month follow-up period.

This treatment modality may benefit physicians and patients encountering recurrent or recalcitrant warts.

 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.

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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.

Elaine K. Orenberg, PhD

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Genital Wart Management: A Partnership Between Physician and Patient