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Condyloma acuminata: treatment strategies for the primary care provider1
HONORABLE MENTION
CONDYLOMA ACUMINATA: TREATMENT STRATEGIES FOR THE PRIMARY CARE PROVIDER Johnnie Wright, Jr., MD, Jeffrey Hines, MD
Condyloma acuminata (genital warts) are a common sexually transmitted disease. The prevalence of genital human papillomavirus (HPV) infection in the general population has been difficult to estimate and is not well established. Approximately one percent of the sexually active population in the United States has genital warts.1 With the advent of new diagnostic modalities such as polymerase chain reaction (PCR), Southern blot, and dot blot, the detection of HPV DNA has been made easier. Bauer and colleagues found that 46% of sexually active women receiving routine annual gynecologic examinations at a college health service were HPV DNA positive using PCR.2 Primary care physicians face the frustrating challenge of treating anogenital HPV infections. To date, no single treatment has been successful in eradicating HPV infections. This review concentrates on the different treatment modalities for genital warts to include surgical/ablative, immunomodulatory, and chemotherapeutic approaches. The advantages, disadvantages, and efficacy of each modality are reviewed. A treatment algorithm is offered. (Prim Care Update Ob/Gyns 2000;7:35– From the Department of Obstetrics and Gynecology, Brooke Army Medical Center, Fort Sam Houston, TX. The views expressed in this manuscript are of the authors and should not be construed as official views of the United States Army or the Department of Defense.
Volume 7, Number 1, 2000
39. © 2000 Elsevier Science Inc. All rights reserved.)
Background All papillomaviruses consist of 55 nm, non-enveloped virions with a double-stranded DNA genome of approximately 8,000 base pairs within an icosahedral capsid. The papillomavirus genome has three functional regions defined as the early, late, and control regions. The early region consists of approximately 4,500 base pairs and contains eight open reading frames (ORF) or genes. These genes are responsible for viral DNA replication, transcription, and cellular transformation. The late region consists of approximately 2,500 base pairs and encodes for the major and minor capsid proteins. The control region consists of 1,000 base pairs and contains the viral origins of DNA replication, promoter elements, and transcription enhancer sequences.3 Over 80 types of HPV have been described. All HPVs infect squamous epithelium or mucous membranes, but different types of HPV show tropism for specific cell types. Human papillomavirus can be divided into anogenital (mucosal) or nongenital cutaneous. Anogenital infections are sexually transmitted. Human papillomavirus has been associated with a number of malignant and nonmalignant diseases. Lorincz and colleagues grouped HPVs into low, intermediate, and
© 2000 Elsevier Science Inc., all rights reserved. 1068-607X/00/$20.00
●
high risk groups.4 Low-risk genotypes 6 and 11 are commonly detected in association with low grade intraepithelial lesions and condylomata and almost never with carcinoma. Intermediate-risk genotypes 31, 33, 35, 51 and 52 may produce high-grade intraepithelial lesions but are less likely to lead to invasive carcinoma. High-risk genotypes 16, 18, 45 and 56 are detected in invasive carcinoma of the cervix.
Diagnosis Condyloma acuminata is usually identified by its pathologic appearance. Lesions can be flat, sessile, pedunculated, or exophytic. When patients present with obvious genital warts, a thorough history should be taken with emphasis on number of sexual partners, other pelvic infections, abnormal Papanicolaou smears, vaginal discharge, vaginal itching, postcoital bleeding, smoking, and contraception. Patients should receive a thorough evaluation of the lower genital tract. A colposcopic examination, screening examination for sexually transmitted diseases, and a Papanicolaou smear should be performed for every patient that presents with clinically obvious genital warts. After thorough examination, a biopsy of the lesion should be performed if atypical lesions are present or a neoplastic process is suspected. After the diagnosis has been established, treatment can be initiated.
PII S1068-607X(00)00038-4
35
WRIGHT, JR AND HINES Table 1. Summary of Selected Data of Treatment Modalities for Condyloma Acuminata Treatment Trichloroacetic acid Podophyllin Podofilox 5-Fluorouracil/Adrenaline Excision Electrodesiccation CO2 Laser Ablation Cryotherapy ␣ Interferon Imiquimod
Success rates (%)
Recurrence rates (%)
References
81 17 74 55 93 90 91 71–88 25 37–52
36 25 33 43–50 29 25 16 39 NR 13–19
6 7 8 9 10 7 11 6,7 12 13,14
CO2 ⫽ Carbon dioxide, NR ⫽ Not recorded.
Treatment Before treatment is initiated, patients should be counseled that genital warts present secondary to HPV infection and they are considered to be sexually transmitted. Available modalities should be discussed with emphasis that clinical data documents recurrence and spontaneous regression in 10 –30% of cases.5 Table 1 summarizes selected published data on treatment modalities.
A treatment algorithm is offered in Figure 1. If initial treatment fails or the disease process worsens, a biopsy should be performed if not previously done. At this point, the primary care provider should consider consultation with a gynecologic specialist. Patients should be counseled on the importance of lifestyle modification and contraception. Sexual partners should be referred for treatment of HPV and other genital infections.
Figure 1. Algorithm for treatment of genital warts. CO2 ⫽ carbon dioxide; DM ⫽ diabetes mellitus; 5-FU ⫽ 5-fluorouracil; HIV ⫽ Human immunodeficiency syndrome; LEEP ⫽ Loop Electricosurgical Excision Procedure. 36
CHEMOTHERAPEUTIC Chemotherapeutic therapies available for treatment of genital warts include trichloracetic acid (TCA), podophyllin, podofilox, and 5-flourouracil. The mechanism of action is either chemodestructive or antiproliferative. All agents have been shown to be equally efficacious. TRICHLOROACETIC ACID (TCA) Trichloroacetic acid is a caustic agent that, when neutralized, leads to tissue destruction. The acetic acid is neutralized by water; therefore, TCA may be offered as the first line of treatment for small mucosal lesions. An 80 – 85% solution is directly applied to the lesion in the physician’s office. Treatment can be repeated weekly. Advantages include its inexpensive cost, lack of systemic toxicity, and ability to be used during pregnancy. Disadvantages include pain and burning at time of application, lack of control of depth of penetration, and early recurrence of lesions. Colposcopy may be helpful in trying to determine depth of penetration. Godley et al published an 81% clearance rate with a 36% recurrence rate within two months of treatment.6 This trial also provided data that cryotherapy was equally efficacious to TCA without the local side effects. PODOPHYLLIN The local application of podophyllin has been the mainstay for many years. The active resin is derived from the plants podophylum emoli and podophylum peltatum. It acts as an antimitotic agent that arrests cell duplication. A 10 –25% solution of podophyllin in tincture of benzoin is used. The solution is applied directly to cutaneous lesions and patients are instructed to wash the treated area in three to six hours. Patients may receive repeated applications over a period of four weeks. Advantages include Prim Care Update Ob/Gyns
CONDYLOMA ACUMINATA TREATMENT STRATEGIES
low cost, easy applicability, and mild local effect at time of application. Disadvantages are bone marrow depression and neurotoxicity when applied to large mucosal areas (contraindicated on mucosal surfaces), and reliance on patient to prevent local symptoms, high recurrence rate, and inability to be used in pregnancy. Careful attention during application is critical since podophyllin is antimitotic and can affect surrounding normal tissue. In a clinical trial comparing the use of podophyllin, cryotherapy, and electrodesiccation for the treatment of genital warts, podophyllin was shown to have a clearance rate of 17% at three months, and electrodesiccation was superior to podophyllin in the treatment of genital warts.7 PODOFILOX (PODOPHYLLOTOXIN) Podofilox 0.5% solution is approved by the Federal Drug Administration (FDA) for patient selfapplication. Its mechanism of action is antimitotic. Treatment of external genital warts includes twice daily application of solution for three days followed by a fourday rest period. This cycle can be repeated four times. Advantages of podofilox include self-application, standardized formulation, and low risk for systemic toxicity. Disadvantages include inability to use during pregnancy, inability to be used on mucosal surfaces, and high recurrence rate. Greenberg et al document complete clearance in 74% of patients with recurrence occurring in approximately one-third of treated patients within four weeks of treatment.8 The most commonly reported side effect in each clinical trial is local irritation. 5-FLOUROURACIL 5-fluorouracil (5-FU) is a pyrimidine antimetabolite and is well known for treatment of vaginal condylomata. It has not been approved by the FDA for treatment of genital warts. In a randomized, double Volume 7, Number 1, 2000
blind, controlled trial by Swinehart et al, data suggest that use of intralesional 5-FU combined with epinephrine offers some promise in the treatment of recalcitrant genital warts.9 In this trial, complete clearance rates of 36%, 13%, and 8% were reported in patients treated with 5-FU gel, 5-FU solution, and placebo respectively. Complete clearance rates in the groups treated with 5-FU gel plus epinephrine, 5-FU solution plus epinephrine solution, and epinephrine solution alone were 55%, 41%, and 17% respectively. This suggests that epinephrine may play a synergistic role in clearance. Recurrence rates of 43–50% were documented for patients treated with 5-FU gel. Disadvantages of 5-FU are lack of evidence-based data that suggest efficacy for the treatment of anogenital warts and local irritation. Its use is contraindicated in pregnancy.
SURGICAL/ABLATIVE Surgical approaches to the treatment of condylomata include simple surgical excision, electrodesiccation, loop electricosurgical excision procedure, carbon dioxide (CO2) laser ablation, and cryotherapy. All modalities offer comparable efficacy and all are complicated by recurrence. EXCISION Simple excision is an option for the patient with genital warts few in number and small in size. It can easily be accomplished in an office setting with a local anesthetic. Jensen showed a 93% clearance rate with 29% recurrence one-year post treatment with simple excision.10 Disadvantages include the need for anesthesia, surgical cost, and longer healing time. ELECTRODESICCATION Stone et al published data from a randomized control trial comparing podophyllin, electrodesiccation, and cryotherapy that showed elec-
trodesiccation to be more efficacious than cryotherapy and podophyllin. 7 Advantages include clearance rate of greater than 90%. Disadvantages include need for anesthesia, surgical skill, recurrence, and equipment costs. LOOP ELECTRICOSURGICAL EXCISION PROCEDURE Loop electricosurgical excision procedure is best known for the treatment of cervical neoplasia. The major disadvantages of loop electricosurgical excision procedure include equipment costs, surgical costs, bleeding, infection, and longer healing times. LASER ABLATION The laser of choice is CO2. This approach destroys the HPV through vaporization. Calkins et al report a 91% complete clearance rate with 16% recurrence.11 Disadvantages include operative and equipment costs, increased healing time, postoperative pain, ulceration, and scar formation. CRYOTHERAPY Cryotherapy using liquid nitrogen has been shown to be efficacious for the treatment of condylomata. The target lesion is frozen resulting in tissue destruction. A number of selected studies report a clearance rate from 71– 88%.6,7 Comparative studies with podophyllin show a clearance rate of 55% versus 17% three months post treatment. The advantages of cryotherapy include ease of administration, low cost and low number of applications. Disadvantages include pain at site of administration and recurrence.
IMMUNOMODULATORY INTERFERON (INF) Interferon ␣, , and ␥ have been offered for treatment of HPV. Different routes of administration, from systemic to topical, have been researched. Intralesional INF has efficacy in the treatment of recalcitrant genital warts, but recurrence is 37
WRIGHT, JR AND HINES
high. Recent data from a large randomized trial show monotherapy with IFN and combination ␣ and ␥ IFN equally efficacious.12 Disadvantages to therapy include cost, fever, “flu-like” symptoms, leukopenia, thrombocytopenia, abnormal liver function tests, and high recurrence. IMIQUIMOD Imiquimod, an immune response modifier, is another treatment modality that has been found to be efficacious for the treatment of condylomata. Imiquimod’s activity is mediated through the production of cytokines, including interferon ␣. Tyring and Arany provide evidence from a controlled molecular study that correlates reduction in lesion size with increasing levels of interferon ␣.13 In clinical trials, complete clearance of warts was seen in 37– 52% and less than 20% recurrence in patients treated with 5% imiquimoid topical cream.14 Higher clearance rates were noted in women versus men. The most commonly expressed side effects were local reactions including erythema, burning, itching, tenderness, and flaking. Advantages of imiquimod treatment include patient selfapplicability, lack of systemic effects, and a favorable safety profile.
FUTURE PROSPECTS FOR TREATMENT Better understanding of HPVs have led clinicians and scientists to innovative approaches to prevention and eradication of HPV infection. Current efforts are focused on development of prophylactic vaccines to prevent HPV infection and its sequelae. The use of recombinant viral-like particles (VLPs) in animal models has offered hope for a human vaccine.15 Further studies are needed to address prophylatic vaccine strategies. With the complexity of HPV, including the existence of 80 different subtypes, the challenge lies in the development of a vaccine with adequate specificity. Issues of 38
mutations, HPV type variants, and cross-relatedness all need to be addressed.
Discussion It has been established that the traditional goals of therapy for sexually transmitted diseases, eradication of infection, elimination of symptoms, prevention of long-term sequelae, and interruption of transmission may not be completely applicable to genital warts at this time. Treatment goals are therefore focused on eliminating physical and psychosocial stressors associated with genital warts. Condylomata are often disfiguring and disrupt the patient’s sex life as they can cause itching, burning, pain, and postcoital bleeding. In summary, there are a number of different modalities that have been introduced for the treatment of condylomata acuminata. All methods show similar efficacy with limitations being toxicity, local effects, and recurrence (Table 1). Current therapies, with the exception of interferon and imiquimod, focus on destruction of the visible lesion with an emphasis on providing patient comfort and decreasing the spread of disease. As stated earlier, these methods have been limited by high recurrence rates. Immunomodulating agents address viral load and are focused on eradication of the underlying cause of the visible lesion. Interferon has been limited in its success secondary to cost, toxicity, and inability for patient self-application. Imiquimod offers self-application and tolerable local effects with acceptable recurrence rates. As primary care physicians and scientists, we are challenged to develop new and more effective strategies to treat and eradicate HPV infection. In an era of managed care with emphasis on evidence-based and cost-effective treatments, a treatment algorithm is offered (Fig-
ure 1). The algorithm serves only as a guide for the treatment of external genital warts. Treatment options should be discussed with the patient, and individualized to meet the satisfaction of the patient and the physician. Pregnant patients and immunocompromised patients fall into a special category and treatment should be recommended accordingly. Patient counseling is an important aspect of treatment for genital warts. Prevention should be emphasized to patients and lifestyle changes should be implemented as appropriate. As primary care physicians, our approach to the treatment of condyloma acuminata should be multidisciplinary. Current treatment modalities should be combined with counseling, lifestyle modification, and a quest for new and innovative approaches. References 1. Koutsky LA, Galloway DA, Holmes KK. Epidemiology of genital human papillomavirus infection. Epidemiol Rev 1988;10:122–163. 2. Bauer HM, Ting Y, Greer CE, et al. Genital human papillomavirus infection in female university students as determined by a PCR-based method. JAMA 1991;265:472– 477. 3. Schegel R. Papillomaviruses and human cancer. Semin Virol 1990;1: 297–306. 4. Lorincz AT, Reid R, Jensen AB, Greenberg MD, Lancaster W, Kurman RJ. Human papillomavirus infection of the cervix: relative risk of 15 common anogenital types. Obstet Gynecol 1992;79:328 –337. 5. Ferenczy A, Mitao M, Nagai N, Silverstein SJ, Crum CP. Latent papillomavirus and recurring genital warts. N Engl J Med 1985;313:784 – 788. 6. Godley MJ, Bradbeer CS, Gellan M, Thin RNT. Cryotherapy compared with trichloroacetic acid in treating genital warts. Genitourin Med 1987; 63:390 –392. 7. Stone KM, Becker TM, Hadgu A, Kraus SJ. Treatment of external genital warts: a randomised clinical trial comparing podophyllin, cryotherapy, and electrodesiccation. Genitourin Med 1990;66:16 –19. Prim Care Update Ob/Gyns
CONDYLOMA ACUMINATA TREATMENT STRATEGIES 8. Greenberg MD, Rutledge LH, Reid R, Berman NR, Precop SL, Elswick RK. A double-blind, randomized trial of 0.5% podofilox and placebo for the treatment of genital warts in women. Obstet Gynecol 1991;77: 735–739. 9. Swinehart JM, Skinner RB, McCarty JM, et al. Development of intralesional therapy with fluorouracil/ adrenaline injectable gel for management of condyloma acuminata: two phase II clinical studies. Genitourin Med 1997;73:481– 487. 10. Jensen SL. Comparison of podophyllin application with simple excision in clearance and recurrence of perianal condyloma acuminata. Lancet 1985;2(8465):1146 –1148. 11. Calkins JW, Masterson BJ, Magrina
Volume 7, Number 1, 2000
JF, Capen CV. Management of condyloma acuminata with the carbon dioxide laser. Obstet Gynecol 1982; 59:105–108. 12. Trinza Z, Evans T, Bruce S, Hatch K, Tyring SK. A randomized phase II study comparing four different interferon therapies in patients with recalcitrant condylomata acuminata. Sex Transm Dis 1998 Aug; 25(7):361–365. 13. Tyring SK, Arany I, Stanley MA, et al. A randomized, controlled molecular study of condylomata acuminata clearance during treatment with imiquimod. J Infect Dis 1998;178:551–555. 14. Beutner KR, Tyring SK, Trofatter KF, et al. Imiquimod, a patientapplied immune-response modifier
for treatment of external genital warts. Antimicrob Agents Chemother 1998;42(4):789 –94. 15. Breitburd F, Kirnbauer R, Hubbert N, Nonenmacher B, Trin-Dinh-Desmarquet, Orth G. Immunization with virus-like particles from cottontail rabbit papillomavirus (CRPV) can protect against experimental CRPV infection. J Virol 1995;69: 3959 –3963.
Address correspondence and reprint requests to Jeffrey Hines, MD, LTC, USA, The Department of Gynecologic Oncology, Brooke Army Medical Center, 3851 Roger Brooke Drive, Fort Sam Houston, Texas 78234-6200.
39
CONDYLOMA ACUMINATA: TREATMENT STRATEGIES FOR THE PRIMARY CARE PROVIDER Johnnie Wright, Jr., MD, Jeffrey Hines, MD
Condyloma acuminata (genital warts) are a common sexually transmitted disease. The prevalence of genital human papillomavirus (HPV) infection in the general population has been difficult to estimate and is not well established. Approximately one percent of the sexually active population in the United States has genital warts.1 With the advent of new diagnostic modalities such as polymerase chain reaction (PCR), Southern blot, and dot blot, the detection of HPV DNA has been made easier. Bauer and colleagues found that 46% of sexually active women receiving routine annual gynecologic examinations at a college health service were HPV DNA positive using PCR.2 Primary care physicians face the frustrating challenge of treating anogenital HPV infections. To date, no single treatment has been successful in eradicating HPV infections. This review concentrates on the different treatment modalities for genital warts to include surgical/ablative, immunomodulatory, and chemotherapeutic approaches. The advantages, disadvantages, and efficacy of each modality are reviewed. A treatment algorithm is offered. (Prim Care Update Ob/Gyns 2000;7:35– From the Department of Obstetrics and Gynecology, Brooke Army Medical Center, Fort Sam Houston, TX. The views expressed in this manuscript are of the authors and should not be construed as official views of the United States Army or the Department of Defense.
Volume 7, Number 1, 2000
39. © 2000 Elsevier Science Inc. All rights reserved.)
Background All papillomaviruses consist of 55 nm, non-enveloped virions with a double-stranded DNA genome of approximately 8,000 base pairs within an icosahedral capsid. The papillomavirus genome has three functional regions defined as the early, late, and control regions. The early region consists of approximately 4,500 base pairs and contains eight open reading frames (ORF) or genes. These genes are responsible for viral DNA replication, transcription, and cellular transformation. The late region consists of approximately 2,500 base pairs and encodes for the major and minor capsid proteins. The control region consists of 1,000 base pairs and contains the viral origins of DNA replication, promoter elements, and transcription enhancer sequences.3 Over 80 types of HPV have been described. All HPVs infect squamous epithelium or mucous membranes, but different types of HPV show tropism for specific cell types. Human papillomavirus can be divided into anogenital (mucosal) or nongenital cutaneous. Anogenital infections are sexually transmitted. Human papillomavirus has been associated with a number of malignant and nonmalignant diseases. Lorincz and colleagues grouped HPVs into low, intermediate, and
© 2000 Elsevier Science Inc., all rights reserved. 1068-607X/00/$20.00
●
high risk groups.4 Low-risk genotypes 6 and 11 are commonly detected in association with low grade intraepithelial lesions and condylomata and almost never with carcinoma. Intermediate-risk genotypes 31, 33, 35, 51 and 52 may produce high-grade intraepithelial lesions but are less likely to lead to invasive carcinoma. High-risk genotypes 16, 18, 45 and 56 are detected in invasive carcinoma of the cervix.
Diagnosis Condyloma acuminata is usually identified by its pathologic appearance. Lesions can be flat, sessile, pedunculated, or exophytic. When patients present with obvious genital warts, a thorough history should be taken with emphasis on number of sexual partners, other pelvic infections, abnormal Papanicolaou smears, vaginal discharge, vaginal itching, postcoital bleeding, smoking, and contraception. Patients should receive a thorough evaluation of the lower genital tract. A colposcopic examination, screening examination for sexually transmitted diseases, and a Papanicolaou smear should be performed for every patient that presents with clinically obvious genital warts. After thorough examination, a biopsy of the lesion should be performed if atypical lesions are present or a neoplastic process is suspected. After the diagnosis has been established, treatment can be initiated.
PII S1068-607X(00)00038-4
35
WRIGHT, JR AND HINES Table 1. Summary of Selected Data of Treatment Modalities for Condyloma Acuminata Treatment Trichloroacetic acid Podophyllin Podofilox 5-Fluorouracil/Adrenaline Excision Electrodesiccation CO2 Laser Ablation Cryotherapy ␣ Interferon Imiquimod
Success rates (%)
Recurrence rates (%)
References
81 17 74 55 93 90 91 71–88 25 37–52
36 25 33 43–50 29 25 16 39 NR 13–19
6 7 8 9 10 7 11 6,7 12 13,14
CO2 ⫽ Carbon dioxide, NR ⫽ Not recorded.
Treatment Before treatment is initiated, patients should be counseled that genital warts present secondary to HPV infection and they are considered to be sexually transmitted. Available modalities should be discussed with emphasis that clinical data documents recurrence and spontaneous regression in 10 –30% of cases.5 Table 1 summarizes selected published data on treatment modalities.
A treatment algorithm is offered in Figure 1. If initial treatment fails or the disease process worsens, a biopsy should be performed if not previously done. At this point, the primary care provider should consider consultation with a gynecologic specialist. Patients should be counseled on the importance of lifestyle modification and contraception. Sexual partners should be referred for treatment of HPV and other genital infections.
Figure 1. Algorithm for treatment of genital warts. CO2 ⫽ carbon dioxide; DM ⫽ diabetes mellitus; 5-FU ⫽ 5-fluorouracil; HIV ⫽ Human immunodeficiency syndrome; LEEP ⫽ Loop Electricosurgical Excision Procedure. 36
CHEMOTHERAPEUTIC Chemotherapeutic therapies available for treatment of genital warts include trichloracetic acid (TCA), podophyllin, podofilox, and 5-flourouracil. The mechanism of action is either chemodestructive or antiproliferative. All agents have been shown to be equally efficacious. TRICHLOROACETIC ACID (TCA) Trichloroacetic acid is a caustic agent that, when neutralized, leads to tissue destruction. The acetic acid is neutralized by water; therefore, TCA may be offered as the first line of treatment for small mucosal lesions. An 80 – 85% solution is directly applied to the lesion in the physician’s office. Treatment can be repeated weekly. Advantages include its inexpensive cost, lack of systemic toxicity, and ability to be used during pregnancy. Disadvantages include pain and burning at time of application, lack of control of depth of penetration, and early recurrence of lesions. Colposcopy may be helpful in trying to determine depth of penetration. Godley et al published an 81% clearance rate with a 36% recurrence rate within two months of treatment.6 This trial also provided data that cryotherapy was equally efficacious to TCA without the local side effects. PODOPHYLLIN The local application of podophyllin has been the mainstay for many years. The active resin is derived from the plants podophylum emoli and podophylum peltatum. It acts as an antimitotic agent that arrests cell duplication. A 10 –25% solution of podophyllin in tincture of benzoin is used. The solution is applied directly to cutaneous lesions and patients are instructed to wash the treated area in three to six hours. Patients may receive repeated applications over a period of four weeks. Advantages include Prim Care Update Ob/Gyns
CONDYLOMA ACUMINATA TREATMENT STRATEGIES
low cost, easy applicability, and mild local effect at time of application. Disadvantages are bone marrow depression and neurotoxicity when applied to large mucosal areas (contraindicated on mucosal surfaces), and reliance on patient to prevent local symptoms, high recurrence rate, and inability to be used in pregnancy. Careful attention during application is critical since podophyllin is antimitotic and can affect surrounding normal tissue. In a clinical trial comparing the use of podophyllin, cryotherapy, and electrodesiccation for the treatment of genital warts, podophyllin was shown to have a clearance rate of 17% at three months, and electrodesiccation was superior to podophyllin in the treatment of genital warts.7 PODOFILOX (PODOPHYLLOTOXIN) Podofilox 0.5% solution is approved by the Federal Drug Administration (FDA) for patient selfapplication. Its mechanism of action is antimitotic. Treatment of external genital warts includes twice daily application of solution for three days followed by a fourday rest period. This cycle can be repeated four times. Advantages of podofilox include self-application, standardized formulation, and low risk for systemic toxicity. Disadvantages include inability to use during pregnancy, inability to be used on mucosal surfaces, and high recurrence rate. Greenberg et al document complete clearance in 74% of patients with recurrence occurring in approximately one-third of treated patients within four weeks of treatment.8 The most commonly reported side effect in each clinical trial is local irritation. 5-FLOUROURACIL 5-fluorouracil (5-FU) is a pyrimidine antimetabolite and is well known for treatment of vaginal condylomata. It has not been approved by the FDA for treatment of genital warts. In a randomized, double Volume 7, Number 1, 2000
blind, controlled trial by Swinehart et al, data suggest that use of intralesional 5-FU combined with epinephrine offers some promise in the treatment of recalcitrant genital warts.9 In this trial, complete clearance rates of 36%, 13%, and 8% were reported in patients treated with 5-FU gel, 5-FU solution, and placebo respectively. Complete clearance rates in the groups treated with 5-FU gel plus epinephrine, 5-FU solution plus epinephrine solution, and epinephrine solution alone were 55%, 41%, and 17% respectively. This suggests that epinephrine may play a synergistic role in clearance. Recurrence rates of 43–50% were documented for patients treated with 5-FU gel. Disadvantages of 5-FU are lack of evidence-based data that suggest efficacy for the treatment of anogenital warts and local irritation. Its use is contraindicated in pregnancy.
SURGICAL/ABLATIVE Surgical approaches to the treatment of condylomata include simple surgical excision, electrodesiccation, loop electricosurgical excision procedure, carbon dioxide (CO2) laser ablation, and cryotherapy. All modalities offer comparable efficacy and all are complicated by recurrence. EXCISION Simple excision is an option for the patient with genital warts few in number and small in size. It can easily be accomplished in an office setting with a local anesthetic. Jensen showed a 93% clearance rate with 29% recurrence one-year post treatment with simple excision.10 Disadvantages include the need for anesthesia, surgical cost, and longer healing time. ELECTRODESICCATION Stone et al published data from a randomized control trial comparing podophyllin, electrodesiccation, and cryotherapy that showed elec-
trodesiccation to be more efficacious than cryotherapy and podophyllin. 7 Advantages include clearance rate of greater than 90%. Disadvantages include need for anesthesia, surgical skill, recurrence, and equipment costs. LOOP ELECTRICOSURGICAL EXCISION PROCEDURE Loop electricosurgical excision procedure is best known for the treatment of cervical neoplasia. The major disadvantages of loop electricosurgical excision procedure include equipment costs, surgical costs, bleeding, infection, and longer healing times. LASER ABLATION The laser of choice is CO2. This approach destroys the HPV through vaporization. Calkins et al report a 91% complete clearance rate with 16% recurrence.11 Disadvantages include operative and equipment costs, increased healing time, postoperative pain, ulceration, and scar formation. CRYOTHERAPY Cryotherapy using liquid nitrogen has been shown to be efficacious for the treatment of condylomata. The target lesion is frozen resulting in tissue destruction. A number of selected studies report a clearance rate from 71– 88%.6,7 Comparative studies with podophyllin show a clearance rate of 55% versus 17% three months post treatment. The advantages of cryotherapy include ease of administration, low cost and low number of applications. Disadvantages include pain at site of administration and recurrence.
IMMUNOMODULATORY INTERFERON (INF) Interferon ␣, , and ␥ have been offered for treatment of HPV. Different routes of administration, from systemic to topical, have been researched. Intralesional INF has efficacy in the treatment of recalcitrant genital warts, but recurrence is 37
WRIGHT, JR AND HINES
high. Recent data from a large randomized trial show monotherapy with IFN and combination ␣ and ␥ IFN equally efficacious.12 Disadvantages to therapy include cost, fever, “flu-like” symptoms, leukopenia, thrombocytopenia, abnormal liver function tests, and high recurrence. IMIQUIMOD Imiquimod, an immune response modifier, is another treatment modality that has been found to be efficacious for the treatment of condylomata. Imiquimod’s activity is mediated through the production of cytokines, including interferon ␣. Tyring and Arany provide evidence from a controlled molecular study that correlates reduction in lesion size with increasing levels of interferon ␣.13 In clinical trials, complete clearance of warts was seen in 37– 52% and less than 20% recurrence in patients treated with 5% imiquimoid topical cream.14 Higher clearance rates were noted in women versus men. The most commonly expressed side effects were local reactions including erythema, burning, itching, tenderness, and flaking. Advantages of imiquimod treatment include patient selfapplicability, lack of systemic effects, and a favorable safety profile.
FUTURE PROSPECTS FOR TREATMENT Better understanding of HPVs have led clinicians and scientists to innovative approaches to prevention and eradication of HPV infection. Current efforts are focused on development of prophylactic vaccines to prevent HPV infection and its sequelae. The use of recombinant viral-like particles (VLPs) in animal models has offered hope for a human vaccine.15 Further studies are needed to address prophylatic vaccine strategies. With the complexity of HPV, including the existence of 80 different subtypes, the challenge lies in the development of a vaccine with adequate specificity. Issues of 38
mutations, HPV type variants, and cross-relatedness all need to be addressed.
Discussion It has been established that the traditional goals of therapy for sexually transmitted diseases, eradication of infection, elimination of symptoms, prevention of long-term sequelae, and interruption of transmission may not be completely applicable to genital warts at this time. Treatment goals are therefore focused on eliminating physical and psychosocial stressors associated with genital warts. Condylomata are often disfiguring and disrupt the patient’s sex life as they can cause itching, burning, pain, and postcoital bleeding. In summary, there are a number of different modalities that have been introduced for the treatment of condylomata acuminata. All methods show similar efficacy with limitations being toxicity, local effects, and recurrence (Table 1). Current therapies, with the exception of interferon and imiquimod, focus on destruction of the visible lesion with an emphasis on providing patient comfort and decreasing the spread of disease. As stated earlier, these methods have been limited by high recurrence rates. Immunomodulating agents address viral load and are focused on eradication of the underlying cause of the visible lesion. Interferon has been limited in its success secondary to cost, toxicity, and inability for patient self-application. Imiquimod offers self-application and tolerable local effects with acceptable recurrence rates. As primary care physicians and scientists, we are challenged to develop new and more effective strategies to treat and eradicate HPV infection. In an era of managed care with emphasis on evidence-based and cost-effective treatments, a treatment algorithm is offered (Fig-
ure 1). The algorithm serves only as a guide for the treatment of external genital warts. Treatment options should be discussed with the patient, and individualized to meet the satisfaction of the patient and the physician. Pregnant patients and immunocompromised patients fall into a special category and treatment should be recommended accordingly. Patient counseling is an important aspect of treatment for genital warts. Prevention should be emphasized to patients and lifestyle changes should be implemented as appropriate. As primary care physicians, our approach to the treatment of condyloma acuminata should be multidisciplinary. Current treatment modalities should be combined with counseling, lifestyle modification, and a quest for new and innovative approaches. References 1. Koutsky LA, Galloway DA, Holmes KK. Epidemiology of genital human papillomavirus infection. Epidemiol Rev 1988;10:122–163. 2. Bauer HM, Ting Y, Greer CE, et al. Genital human papillomavirus infection in female university students as determined by a PCR-based method. JAMA 1991;265:472– 477. 3. Schegel R. Papillomaviruses and human cancer. Semin Virol 1990;1: 297–306. 4. Lorincz AT, Reid R, Jensen AB, Greenberg MD, Lancaster W, Kurman RJ. Human papillomavirus infection of the cervix: relative risk of 15 common anogenital types. Obstet Gynecol 1992;79:328 –337. 5. Ferenczy A, Mitao M, Nagai N, Silverstein SJ, Crum CP. Latent papillomavirus and recurring genital warts. N Engl J Med 1985;313:784 – 788. 6. Godley MJ, Bradbeer CS, Gellan M, Thin RNT. Cryotherapy compared with trichloroacetic acid in treating genital warts. Genitourin Med 1987; 63:390 –392. 7. Stone KM, Becker TM, Hadgu A, Kraus SJ. Treatment of external genital warts: a randomised clinical trial comparing podophyllin, cryotherapy, and electrodesiccation. Genitourin Med 1990;66:16 –19. Prim Care Update Ob/Gyns
CONDYLOMA ACUMINATA TREATMENT STRATEGIES 8. Greenberg MD, Rutledge LH, Reid R, Berman NR, Precop SL, Elswick RK. A double-blind, randomized trial of 0.5% podofilox and placebo for the treatment of genital warts in women. Obstet Gynecol 1991;77: 735–739. 9. Swinehart JM, Skinner RB, McCarty JM, et al. Development of intralesional therapy with fluorouracil/ adrenaline injectable gel for management of condyloma acuminata: two phase II clinical studies. Genitourin Med 1997;73:481– 487. 10. Jensen SL. Comparison of podophyllin application with simple excision in clearance and recurrence of perianal condyloma acuminata. Lancet 1985;2(8465):1146 –1148. 11. Calkins JW, Masterson BJ, Magrina
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JF, Capen CV. Management of condyloma acuminata with the carbon dioxide laser. Obstet Gynecol 1982; 59:105–108. 12. Trinza Z, Evans T, Bruce S, Hatch K, Tyring SK. A randomized phase II study comparing four different interferon therapies in patients with recalcitrant condylomata acuminata. Sex Transm Dis 1998 Aug; 25(7):361–365. 13. Tyring SK, Arany I, Stanley MA, et al. A randomized, controlled molecular study of condylomata acuminata clearance during treatment with imiquimod. J Infect Dis 1998;178:551–555. 14. Beutner KR, Tyring SK, Trofatter KF, et al. Imiquimod, a patientapplied immune-response modifier
for treatment of external genital warts. Antimicrob Agents Chemother 1998;42(4):789 –94. 15. Breitburd F, Kirnbauer R, Hubbert N, Nonenmacher B, Trin-Dinh-Desmarquet, Orth G. Immunization with virus-like particles from cottontail rabbit papillomavirus (CRPV) can protect against experimental CRPV infection. J Virol 1995;69: 3959 –3963.
Address correspondence and reprint requests to Jeffrey Hines, MD, LTC, USA, The Department of Gynecologic Oncology, Brooke Army Medical Center, 3851 Roger Brooke Drive, Fort Sam Houston, Texas 78234-6200.
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