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Comparative study of systemic interferon alfa-nl and isotretinoin in the treatment of resistant condylomata acuminata
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Comparative study of systemic interferon alfa-nl and isotretinoin in the treatment of resistant condylomata acuminata Elise A. Olsen, MD, ~ Frances F. Kelly, RN, a Robin T. Vollmer, MD, u Debra A. Buddin, MSN, ~ and Phillip K. Week, PhD ~ Durham and
Research Triangle Park, North Carolina This study evaluated the effectiveness of systemic interferon alfa-nl versus isotretinoin in the treatment of condylomata aeuminata. Patients were randomly assigned interferon alfa-nl, 5 million units, subcutaneously daily for 2 weeks then twice weekly for 4 weeks, or isotretinoin, 1 mg/kg by mouth daily for 6 weeks. Seventeen otherwise healthy men with histologically confirmed condylomata acuminata refractory to standard treatment completed 6 study weeks. Five of nine men (56%) treated with interferon alfa-nl had an objective clinical response (>--50% clearance of baseline disease), with one patient clearing completely. None of the patients treated with isotretinoin alone had an objective response (p = 0.009). Those whose clearing was incomplete with interferon alone were then assigned to interferon therapy three times weekly in combination with daily isotretinoin for 6 weeks, and those receiving isotretinoin were switched to interferon three time~ weekly for 6 weeks. There was continued clearing in all patients in the combination treatment group but in only three of seven in the sequential treatment group. Side effects were common and generally predictable for each drug but were generally not exacerbated when interferon and isotretinoin were used in combination. Parenteral interferon alfa-nl is an effective alternative treatment modality for patients with refractory condylomata acuminata. (J AM ACADDERMATOL1989;20:1023-30.)
Condylomata acuminata, or genital warts, are benign epithelial-derived tumors associated with h u m a n papillomavims infection. ~ These verrucous growths occur frequently in sexually active men and women and appear both externally on the penile, vulvar, or perianal areas and internally on the vaginal vault/cervix or anal canal. Traditional forms of therapy involve local obliteration of visibly affected tissue by topical application of podophyllin, trichloroacetic acid, or 5-fluorouracil or by
From the Division of Dermatology, Departments of Medicine~ and Pathology, b Duke University Medical Center, Durham, and the Department of Infectious Diseases, Burroughs WelIcome,~ Research Triangle Park. Supported in part by a grant from the Burroughs Wellcome Company. Accepted for publication May 31, 1988. Reprint requests: Elise A. Olsen, MD, Box 3294, Duke University Medical Center, Durham, NC 27710.
surgical destruction with electrocautery, cryosurgery, carbon dioxide laser, or scalpel excision. Local treatment is often difficult because of the associated pain, the difficulty in achieving complete eradication, and the high recurrence rate. The recalcitrant nature of genital warts m a y be related to either the lack of treatment of certain "privileged" sites, for example, the mucosal surfaces, or perhaps latent virus that may exist in normalappearing skin. 2 Viral D N A has been detected in normal-appearing tissue after destruction of visible warts by carbon dioxide laser.2 A systemic form of treatment for condylomata acuminata may more completely eradicate the virus, thus leading to more lasting remissions. Patients in whom repeated conventional treatment modalities fail are prime candidates for alternative therapy. Interferon is an inducible protein with inherent antiviral, antiproliferative, and immunomodulatory activities, a Alpha or leukocyte-derived interferon 1023
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Olsen et al. Oh,err-lion
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Fig. 1. Schema of treatment schedule for condylomata acuminata. INF, interferon; MU, million units.
has been used in topical,* intralesional, .9 or parenteral*. 10-16forms to treat various types of human papillomavirus-related growths. In previous studies using parenteral interferon alfa-nl (Wellferon), 65% to 94% of patients with condylomata acuminata refractory to standard therapies had objective r e s p o n s e s t, i0-i i
Retinoids are vitamin A derivatives that also have antiproliferative activities on various epithelial tissues. These agents have some effect on human papillomavirus-infected tissue as shown in uncontrolled studies of small cohorts of patients with common warts, tT,~8 epidermodysplasia verruciformis, 19,2~ or laryngeal papillomatosis. 2~ No prior study has addressed the efficacy of retinoids in condylomata acuminata. The purpose of this study was to evaluate the safety and efficacy of interferon alfa-nl or isotretinoin as primary therapy for recalcitrant condylomata acuminata in men. A secondary treatment arm tested possible synergistic activity a n d / o r potential additive toxicities of the combination of these two agents to assess those patients who failed to respond to interferon alfa-nl alone. *Ikic D, Bosnie N, Smerdel S, Jusic D, Soos E, Delimar N. Double blind clinical study with human ieukocyte inLerferon in the tlaeragy of condylomata acuminata. Proceedings from the Symposium on Clinical Use of Interferon, Ninth International Immunobiological Symposium, Zagreb, Yugoslavia, October 1-2, 1975:229-33. ~'Trofatter KF, Olsen EA, Kucera PR, et al. Combination of NSAID and Wellferon: a controlled clinical trial in genital warts. Bio Interferon System 1985;471-7.
METHODS Subjects Men older than 18 years of age with condylomata acuminata for at least 3 months that was refractory to at least two treatments with traditional therapies were eligible for this study. Genital warts were confirmed histologicaliy by biopsy of affected tissue; patients with evidence of mafignant degeneration were excluded. Patients must have been in good health, excluding condylomata, as determined by a preentry history and physical examination. Patients with major immunodeficiencies or those who had received parenteral or oral steroids, radiotherapy, or immunosuppressive medications within 3 months of study entry were excluded. Laboratory screening tests performed before entry included complete blood cell count with differential and platelets, electrolytes, liver function tests, and urinalysis. Patients with abnormal results were excluded from the study. No patient with a positive human immunodeficiency virus antibody screen by enzyme-linked irnmunosorbont assay and confirmatory neutralizing antibody test was entered in the study. Fasting serum lipids were drawn before entry. If the cholesterol or triglyceride levels were greater than 300 mg/dl on two occasions, the patient was not enrolled. Lateral spine x-ray films were done at baseline to rule out changes that could be radiologicaUy confused with any subsequent retinoidrelated changes. Protocol. Patients who met entry criteria and provided signed, informed consent were enrolled in the study. Patients were assigned by a computer-generatedrandom code to one of two treatment groups (Fig. 1). One group of patients received interferon alfa-nl subcutaneously at a dosage of 5 million units daily for 2 weeks, then three times per week for an additional 4 weeks. The other
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Interferon alfa-nl and isotretinoin in the treatment of condylomata acuminata 1025
Table I. Demographic characteristics of patients with condylomata acuminata treated with interferon alfa-nl and/or isotretinoin
Treatment group InterferOn(n = 9)alfa'nl [ Age (yr): Mean (range) Race Disease duration (yr) Mean, median (yr) Location of warts Penile Perirectal Both
lsotretinoin (n = 8)
33.4 (19-55) White 6; black, 3 0.25-20 3.6, 1.4
27.6 (20-35) White, 6; black, 1; Oriental, 1 0.33-5 1.5, 0.79
4 4 1
4 2 2
group received isotretinoin (Accutane) at a dosage of 1 mg/kg daily by mouth. At the end of the 6-week treatment period, response was assessed by bidimensional measurements of lesions. Those judged to be 100% clear of visible condylomata were considered to have a complete response (CR). Those with >__50%clearing of condylomata were considered partial responders (PR), and those with >__25%but less than 50% clearing were considered minimal responders (MR). Those with <25% clearing of lesion area were considered nonresponders (NR). Patients initially treated with interferon alfa-nl, who showed less than a complete response after 6 weeks, were offered an additional 6 weeks of interferon, 5 million units three times weekly, plus I mg/kg isotretinoin daily. Patients who showed less than a complete response after 6 weeks of isotretinoixt alone were switched to interferon alfa-nl, 5 million units three times per week for 6 weeks. All patients were then observed for an additional 12 weeks after completion of drug therapy. Patients who had a complete response at the end of the initial 6 weeks of treatment continued without medication and were observed for an additional 18 weeks. Patients who never completely cleared of disease or who relapsed by the end of week 24 of the study were offered the option of additional treatment with interferon alfa-ni, 5 million units subcutaneously three times per week, plus isotretinoin, 1 mg/kg by mouth daily, for a maximum of 12 weeks. Assessment of efllcaey. Patients returned at 2-week intervals during the active drug treatment periods and monthly during the observation periods. Lesions were mapped, and bidimensiona[ measurements of anatomically localized condylomata were recorded at each visit. Standardized photographs were taken at each evaluation to confirm disease assessments. Assessment of safety. Baseline laboratory tests, excluding human immunodeficiency virus antibody,
were repeated every 2 weeks during active drug treatment and at the end of the observation periods. Lateral spine x-ray studies were repeated at study completion. Statistical analysis. Total lesion areas were computed for each patient and then summarized by evaluation week. The difference in percentage change from baseline at week 6 was compared for the primary treatment groups (i.e., interferon alfa-nl vs isotretinoin). Differences between groups were assessed with the use of Wilcoxon's rank sum test. RESULTS Efficacy Twenty-one men with histologieaUy confirmed condylomata acurninata refractory to standard treatment entered the study. Ages ranged from 19 to 55 years (mean, 30.4 years). Fifteen men were white, five were black, and one was Oriental. The duration of genital warts ranged from 3 months to 20 years. Prior treatment included podophyUin in 20 patients, liquid nitrogen in 7 patients, surgery or laser in 2 patients each, electrodesiccation in 3 patients, and triehloroacetic acid in 1 patient. Four patients did not complete primary therapy. One patient initially randomized to interferon alfa-nl therapy had elevated triglycerides at entry and on repeat testing, and he was withdrawn from the study. A second patient receiving interferon alfa-nl declined therapy after 2 weeks because of symptomatic side effects. One patient who was taking isotretinoin alone was lost to follow-up after 2 weeks, and another patient dropped out after 4 weeks because of symptomatic side effects. Seventeen men who completed 6 weeks of the study were evaluated for safety and efficacy. Nine initially were randomized to interferon alfa-nl and
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Table II. Responses of patients treated with interferon alfa-nl followed by combination therapy Percentage change from baseline surface area of
eondylmnata Crossover to I inlerferon and
Disease Patient
duration
No. 1 2 3 4 5 6 7 8 9
P,
19 33 43 44 34 25 21 25 55
Race
(yr)
Location
Interferon
isotretinoin
W B B W W W W W B
0.5 4.9 1.4 2.0 0.7 0.8 0.3 2.4 20.5
P P,PR PR PR PR PR P P P
44.4 18.3 60.5 50 47.5 55.9 55.8 100 33
69.1 -70.4 67.6 98.4 64.7 98.9 ---
12 wk observation
End of
79.2 -69.1 0 95.1 100 97.1 82.1
Penile;PR, perirectal.
Table III. Response of patients treated sequentially with isotretinoin and interferon alfa-nl
i Patient
No. 10 11 12 13 14 15 16 17
PR,
Age
(yr)
Race
34 21 35 24 28 31 24 23
B W W W W W W O
l'ercentagechangefromImsiline surface area of condylomala Crossover End of 12 wk
Disease duration
(yr)
Location
1.1 0.9 2.1 0.3 0.4 5.2 0.6 0.7
PR P,PR P P PR P P P,PR
lsotretinoin
interferon
observation
20.7 17.1 6.9 3.5 Increase 9.1 Increase Increase
84.8 56.2 -Increase Increase 36.4 Increase Increase
99.4 97.2 ---6.5 --
Perireetal;1", penile.
eight to isotretinoin. Demographic characteristics of each group are shown in Table I. Tables II and III list the patients initially assigned to interferon alfa-nl or isotretinoin therapy, respectively. The data from these patients were used for statistical comparisons as already outlined. The interferon alfa-nl group had a mean reduction from baseline of 52% (range, 18.3%-100%), and the isotretinoin group had a mean increase from baseline of 10.9% (range, -20.7~ These mean values were significantly different ( p = 0.0009). The results indicate that interferon alfa-nl was more effective than isotretinoin in reducing the total lesion area at week 6. Nine patients completed 6 weeks of interferon alfa-nl alone (Table II). One patient showed complete response, four were partial responders, three
were minimal responders, and one showed no response. All patients showed some degree of clinical improvement during the course of interferon a|fa-nl. After initial interferon affa-nl therapy the four partial responders and two of the three minimal responders were switched to combination therapy with interferon plus isotretinoin. At the end of an additional 6 weeks of combined therapy, alI six had further regression of warts, with responses ranging from 64.7% to 98.9% clearing from baseline (Fig. 2). Two of these patients, who initially had partial responses, required discontinuation of interferon alfa-nl during the combination treatment period because of elevated liver function test results. These two men were treated with isotretinoin alone for 4 or 5 weeks. Both showed continued improvement on the single agent. Isotretinoin was
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Interferon alfa-nl and isotretinoin in the treatment of condylomata acuminata 1027
Fig. 2. A, Baseline condylolnata patient 7. B, End of 6 weeks' therapy with interferon alfa-nl. C, End of 6 additional weeks' therapy with interferon alfa-nl plus isotretinoin.
discontinued in two patients because of elevated liver function test results after 2 or 5 weeks of combination therapy. Both patients showed continued improvement with interferon alfa-nl alone. Seven patients were evaluated at the completion of 12 or more weeks of observation after drug discontinuation; two patients had continued regression of genital warts. Four had some regrowth of lesions, but these patients still had 69.1% to 97. 1% decrease in lesion surface area from baseline. Only one patient had complete regrowth of his disease. Table III lists the eight patients treated with isotretinoin alone during the 6 weeks of primary therapy. All were nonresponders. In fact, three patients receiving isotretinoin aione had an increase in lesion area during the 6-week period. The patients with progressive disease and four of the five nonresponders taking isotretinoin alone were switched to interferon alfa-nl alone. At the end of the sequential 6 weeks of interferon alfa-nl therapy, there were two patients with a PR, one patient with minimal response, and four nonresponders. At the completion of 12 weeks of observation without drug therapy, the two patients with partial response had continued, but not complete, clearing (97.2%-99.4% of baseline lesion areas) (Fig. 3, A-C).
Only 3 patients completed an additional 6 weeks in the addendum study in which they received combination therapy. Of those, one patient had a complete response, one patient had slight improvement response, and one patient showed no response.
Safety The known biologic side effects were common and generally predictable for each individual drug. Eight of the nine patients initially receiving interferon alfa-nl and 6 of 7 who were switched from isotretinoin to interferon alfa-nl alone had flulike symptoms (fever, chills, and/or malaise) during initiation of therapy. These side effects tended to dissipate during the first few days. Fifteen of 16 patients who received interferon als as a single agent had headache, and 7 patients had gastrointestinal symptoms (nausea, anorexia, and/or diarrhea). These were generally less severe with a three-times-weekly dosing rather than daily administration. All but one of the patients on an interferon alfa-nl regimen experienced fatigue that persisted throughout treatment, although to a lesser degree on the three-times-weekly schedule. Two patients complained of decreased libido, two of increased irritability, and another had an episode of bizarre behavior at a church revival meeting; only
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Fig. 3. A, Patient 10. Baseline condylomata. B, 12 weeks of therapy (isotretinoin followed by 6 weeks of interferon alfa-nl). C, 3 months after treatment. the latter reaction necessitated the patient's dismissal from the study. One patient had seizures during the addendum study as a result of aseptic meningitis of viral origin. Three patients complained of irritation at the wart site while taking interferon alfa-nl alone. Three patients who began the study with interferon alfa-nl therapy alone and two who were switched to interferon alfa-nl alone showed elevated liver function tests results of more than 1.5 times the normal range. These abnormalities resolved when the dosage of interferon alfa-nl was lowered or discontinued. A mild decrease in white blood cell count was noted in most patients on the interferon alfa-nl regimen, but no clinical complications resulted from these changes. All side effects related to interferon alfa-nl therapy were reversible when the drug was discontinued. All patients who took isotretinoin alone experienced dry skin, dry eyes, and/or cheilitis. Four patients complained of wart irritation, three patients complained of fatigue, two patients noted hair thinning, and one patient complained of joint aches. Three patients had elevation of triglycerides greater than two times baseline. Fatigue and/or malaise were the most common side effects reported by patients originally on an interferon alfa-nl regimen alone who were switched to a combination of interferon alfa-nl and isotretinoin therapy. These effects appeared to be additive. There were no increases in triglyceride nor cholesterol levels dur-
ing the combination therapy from that seen with isotretinoin alone. Liver function test results of three patients receiving the combination were more than 1.5 times the normal limits. One patient's values returned to normal limits when interferon alfa-nl was discontinued, and the other two patients' values returned to normal limits when isotretinoin was discontinued. In general, combination therapy of interferon alfa-nl and isotretinoin was well tolerated. DISCUSSION This study confirms the etlicacy of interferon alfa-nl in treating recalcitrant condylomata acuminata in men. Five of 9 men (56%) treated with 5 million units interferon alfa-nl daily for 2 weeks and then three times weekly for 4 weeks had an objective clinical response (>50% clearance of baseline lesion area). None of the patients treated with isotretinoin alone had an objective response. Comparison of mean percentage changes from baseline lesion areas demonstrated a statistically significant difference between these two groups (p = 0.0009). Two of the 7 patients who were switched from isotretinoin to interferon alfa-nl therapy alone for 6 weeks had objective responses. Previous nonplacebo-controlled studies in both men and women with recalcitrant condylomata acuminata that used an identical dosing schedule,
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Interferon alfa-nl and isotretinoin in the treatment of eondylomata aeuminata 1029
but varying doses of interferon alfa-nl have shown similar efficacy. In studies using 1, 3, or 5 million units/m 2, objective responses of 79%, I~ 90%, ~~and 93.8%, 1~ respectively, have been reported. In this study the complete response rate was one of nine patients (11%) receiving interferon alone versus the 21% to 40% reported in these other studies. Patients treated in the current trial did not have any apparent differences in overall tumor mass, duration of disease, and age compared with the other study populations. However, all subjects in the current study were men versus 84% to 100% female subjects in the earlier studies.~~ ~ We earlier reported ~5a similar disparity in response by sex in a study comparing interferon alfa-nl therapy alone versus interferon plus ibuprofen therapy for recalcitrant genital warts. In that study 68% of the women versus 22% of the men had an objective response. An explanation for the sex difference in response to interferon remains unclear. Douglas et al) 6 reported that the presence of antibody to human immunodeficiency virus correlated significantly with a negative response to intralesional interferon alfa-2b treatments in patients with condyloma. We specifically addressed this potential bias inasmuch as all of our patients were human immunodeficiency virusantibody negative. W e chose to evaluate the possible synergistic effect of retinoids with interferon because of isolated reports of their efficacy in various human papillomavirus-related tumors) 7-2~ Two immunocompromised patients with widespread and debilitating "common" w a r t s 17,18 and five patients with epidermodysplasia verruciformis had marked improvement with etretinate therapy) 9,2~ In addition, isotretinoin was used in five patients with juvenile laryngeal papillomatosis, with a complete response in two patients and a partial response in one patient. 21 The hallmark of human papillomavirus infection is epithelial hyperplasia, 22 and retinoids have an endogenous antiproliferative effect through control of epithelial cell differentiation? 3 Retinoids also have an immunomodulatory effect that we believed may have been of particular benefit in patients with recalcitrant human papillomavirus-related tumors and could complement the same effect seen with interferons. 24 N o patient in this study receiving isotretinoin therapy alone had an objective response. Of the seven patients switched to an interferon alfa-nl
regimen alone after an initial 6 weeks of isotretinoin, only two had an objective response. This is a less favorable response than interferon alfa-nl therapy alone from the outset. An improvement, however, was seen in those men treated with a combination of isotretinoin and interferon alfa-nl for 6 weeks after an initial 6 weeks of interferon alfa-nl alone; their objective response rate increased to 5 of 6 and all had increased clearance. This may be related either to the addition of isotretinoin or to prolonged treatment (12 weeks vs 6 weeks) with interferon alfa-nl. Two large placebo-controlled studies have been published on the intralesional use of interferon alfa-2b. Vance et al. 4 injected 106 or 105 units of interferon alfa-2b or placebo into individual warts three times per week for 3 weeks. At the end of the treatment period no significant difference in response to treatment was seen among the three groups. However, after 9 weeks of posttherapy follow-up, the complete response was 53%, 19%, and 14% in the 106 units interferon, 105 units interferon, and placebo groups, respectively. This study established a threshold interferon level for effective treatment and showed that the improvement may be maximized several weeks after drug discontinuation versus immediately after completion of treatment. Eron et al: conducted a large, placebo-controlled study with the use of 1 million units three times per week for 3 weeks interlesionally and found in the active drug group a 20% complete response rate at week 4 versus a 36% rate at week 16 (13 weeks off the treatment regimen). At this dosage no effect was seen on untreated warts and few side effects were reported, thus making a systemic effect of interferon unlikely:.5 Local injection of a limited number of genital warts may be a reasonable approach to treatment. However, use of interferon in this manner for patients with a large number of warts may be difficult. The total volume of interferon needed to treat many warts effectively probably would result in systemic side effects. In addition, multiple individual injections into genital warts are painful, time-consuming, and expensive. Parenteral treatment with interferon alfa-nl for refractory condylomata acuminata is associated with side effects but, generally, these are well tolerated by patients and dissipate with repeated injections. Patients also are able to administer intramuscular or subcutaneous injections at home, eliminating frequent office
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visits. Most important, systemic interferon alfa-nl therapy may result in significant amelioration or complete clearing of condylomata in patients with persistent and/or locally debilitating disease for which other forms of treatment have been unsuccessful. REFERENCES 1. Gissman L, DeVilliers EM, ZurHansen H. Analysis of human genital warts (condylomata acuminata) and other genital tumors for human papillomavirus type 6 DNA. Int J Cancer 1982;29:143-6. 2. Ferenczy A, Mitao M, Nagai N, Silverstein S J, Crum CP. Latent papillomavirus and recurring genital warts. N Engl J Med 1985;313:784-8. 3. Ringenberg QS, Anderson PC. Interferons in the treatment of skin disease. Int J Dermatol 1986;25:273-9. 4. Vance JC, Bart BJ, Hansen RC, et al. Intralesional recombinant alpha-2 interferon for the treatment of patients with eondyloma acuminatum or verruca plantaris. Arch Dermatol 1986;122:272-7. 5. Eron LJ, Judson F, Tucker S, et al. Interferon therapy for condylomata acuminata. N Engl J Med 1986;315:105964. 6. Gibson JR. Intralesional human lymphoblastoid interferon alpha for the treatment of cutaneous, nongenitaI viral warts. Arch Dermatol 1986;122:1098-9. 7. Gibson JR, Harvey SG. Interferon in the treatment of persistent viral warts. Dermatologica 1984;169:47-8. 8. Berman B, Davis-Reed L, Silverstein L, et al. Treatment of verrucae vulgaris with alpha-2 interferon. J Infect Dis 1986;154:328-30. 9. Geffen JR, Klein R J, Friedman-Kien AE. Intralesional administration of large doses of human leukocyte interferon for the treatment of condylomata acuminata. J Infect Dis 1984;150:612-5. 10. Gall SA, Hughes CE, Trofatter K. Interferon for the therapy of condyloma acuminatum. Am J Obstet Gynecol 1985;153:157-63. 11. Gall SA, Hughes CE, Mounts P, Segriti A, Weck PK, Whisnant JK. Efficacy of human lymphoblastoid interferon in the therapy of resistant condyloma acuminata. Obstet Gynecol 1986;67:643-51. 12. Gross G, Roussaki A, Schopf E, De Villiers EM, Papendick U. Successful treatment of condylomata acuminata and Bowenoid papulosis with subcutaneous injections of
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low-dose recombinant alpha interferon. Arch Dermatol 1986;122:749-50. Androphy El, Dvoretzky I, Maluish A_E, Wallace HJ, Lowy DR. Response of warts in epidermodysplasia verruciformis to treatment with systemic and intralesional alpha interferon. J AM ACA~ DaRMATOL 1984;11:197202. Gross G, Ikenberg H, Roussaki A, Drees N, Schopf E. Systemic treatment of condylomata acuminata with recombinant interferon-alpha-2a: low-dose superior to the high-dose regimen. Chemotherapy 1986;32:537-41. Olsen EA, Trofatter KF, Gall SA, et al. Human lymphoblastoid alpha-interferon in the treatment of refractory condyloma acuminata. J Invest Dermatol 1985;84:359. Douglas Jr JM, Rogers M, Judson FN. The effect of asymptomatic infection with HTLV-III on the response of anogenital warts to intralesional treatment with recombinant alpha 2 interferon. J Infect Dis 1986;154:331-4. Gross G, Pfister H, Hagedorn M, Stahn R. Effect of oral aromatic retinoid (Ro 10-9359) on human papilloma virus-2-induced common warts. Dermatologica 1983; 166:48-53. Boyle J, Dick DC, Mackie RM. Treatment of extensive virus warts with etretinate (Tegison) in a patient with sarcoidosis. Clin Exp Dermatol 1983;8:33-6. Jablonska S, Obalek S, Wolska H, Jarzabek-Chorzelska M. Ro 10-9359 in epidermodysplasia verruciformis. Preliminary report. In: Orfanos CE, Braun-Falco O, Farber EM, Grupper Ch, Polano MK, Schuppli R. Retinoids, advances in basic research and therapy. Berlin: SpringerVerlag, 1981:401-5. Lutzner MA. Oral retinoid treatment of human papillomavirus type 5-induced epidermodysplasia verruciformis. N Engl J Med 1981;302:1091. Alberts DS, Coulthard SW, Meyskens FL. Regression of aggressive laryngeal papillomatosis with 13-cis-retinoic acid (Accutane). J Biol Response Mod 1986;5:124-8. Lutzner MA. The human papillomaviruses. Arch Dermatol 1983;119:631-5. Spore MB. Retinoids: new developments in their mechanism of action as related to control of proliferative diseases. In: Orfanos CE, Braun-Falco O, Farber EM, Grupper Ch, Polano MK, Schuppli R, eds. Retinoids, Advances in Basic Research and Therapy. Berlin: Springer-Verlag, 1981:401-5. Borden EC, Ball LA. Interferons: biochemical, cell growth inhibitory, and immunological effects. Prog Hematol 1981;12:299-339.
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Comparative study of systemic interferon alfa-nl and isotretinoin in the treatment of resistant condylomata acuminata Elise A. Olsen, MD, ~ Frances F. Kelly, RN, a Robin T. Vollmer, MD, u Debra A. Buddin, MSN, ~ and Phillip K. Week, PhD ~ Durham and
Research Triangle Park, North Carolina This study evaluated the effectiveness of systemic interferon alfa-nl versus isotretinoin in the treatment of condylomata aeuminata. Patients were randomly assigned interferon alfa-nl, 5 million units, subcutaneously daily for 2 weeks then twice weekly for 4 weeks, or isotretinoin, 1 mg/kg by mouth daily for 6 weeks. Seventeen otherwise healthy men with histologically confirmed condylomata acuminata refractory to standard treatment completed 6 study weeks. Five of nine men (56%) treated with interferon alfa-nl had an objective clinical response (>--50% clearance of baseline disease), with one patient clearing completely. None of the patients treated with isotretinoin alone had an objective response (p = 0.009). Those whose clearing was incomplete with interferon alone were then assigned to interferon therapy three times weekly in combination with daily isotretinoin for 6 weeks, and those receiving isotretinoin were switched to interferon three time~ weekly for 6 weeks. There was continued clearing in all patients in the combination treatment group but in only three of seven in the sequential treatment group. Side effects were common and generally predictable for each drug but were generally not exacerbated when interferon and isotretinoin were used in combination. Parenteral interferon alfa-nl is an effective alternative treatment modality for patients with refractory condylomata acuminata. (J AM ACADDERMATOL1989;20:1023-30.)
Condylomata acuminata, or genital warts, are benign epithelial-derived tumors associated with h u m a n papillomavims infection. ~ These verrucous growths occur frequently in sexually active men and women and appear both externally on the penile, vulvar, or perianal areas and internally on the vaginal vault/cervix or anal canal. Traditional forms of therapy involve local obliteration of visibly affected tissue by topical application of podophyllin, trichloroacetic acid, or 5-fluorouracil or by
From the Division of Dermatology, Departments of Medicine~ and Pathology, b Duke University Medical Center, Durham, and the Department of Infectious Diseases, Burroughs WelIcome,~ Research Triangle Park. Supported in part by a grant from the Burroughs Wellcome Company. Accepted for publication May 31, 1988. Reprint requests: Elise A. Olsen, MD, Box 3294, Duke University Medical Center, Durham, NC 27710.
surgical destruction with electrocautery, cryosurgery, carbon dioxide laser, or scalpel excision. Local treatment is often difficult because of the associated pain, the difficulty in achieving complete eradication, and the high recurrence rate. The recalcitrant nature of genital warts m a y be related to either the lack of treatment of certain "privileged" sites, for example, the mucosal surfaces, or perhaps latent virus that may exist in normalappearing skin. 2 Viral D N A has been detected in normal-appearing tissue after destruction of visible warts by carbon dioxide laser.2 A systemic form of treatment for condylomata acuminata may more completely eradicate the virus, thus leading to more lasting remissions. Patients in whom repeated conventional treatment modalities fail are prime candidates for alternative therapy. Interferon is an inducible protein with inherent antiviral, antiproliferative, and immunomodulatory activities, a Alpha or leukocyte-derived interferon 1023
Journal
1024
of
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Olsen et al. Oh,err-lion
INF 5 Idr,J
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Fig. 1. Schema of treatment schedule for condylomata acuminata. INF, interferon; MU, million units.
has been used in topical,* intralesional, .9 or parenteral*. 10-16forms to treat various types of human papillomavirus-related growths. In previous studies using parenteral interferon alfa-nl (Wellferon), 65% to 94% of patients with condylomata acuminata refractory to standard therapies had objective r e s p o n s e s t, i0-i i
Retinoids are vitamin A derivatives that also have antiproliferative activities on various epithelial tissues. These agents have some effect on human papillomavirus-infected tissue as shown in uncontrolled studies of small cohorts of patients with common warts, tT,~8 epidermodysplasia verruciformis, 19,2~ or laryngeal papillomatosis. 2~ No prior study has addressed the efficacy of retinoids in condylomata acuminata. The purpose of this study was to evaluate the safety and efficacy of interferon alfa-nl or isotretinoin as primary therapy for recalcitrant condylomata acuminata in men. A secondary treatment arm tested possible synergistic activity a n d / o r potential additive toxicities of the combination of these two agents to assess those patients who failed to respond to interferon alfa-nl alone. *Ikic D, Bosnie N, Smerdel S, Jusic D, Soos E, Delimar N. Double blind clinical study with human ieukocyte inLerferon in the tlaeragy of condylomata acuminata. Proceedings from the Symposium on Clinical Use of Interferon, Ninth International Immunobiological Symposium, Zagreb, Yugoslavia, October 1-2, 1975:229-33. ~'Trofatter KF, Olsen EA, Kucera PR, et al. Combination of NSAID and Wellferon: a controlled clinical trial in genital warts. Bio Interferon System 1985;471-7.
METHODS Subjects Men older than 18 years of age with condylomata acuminata for at least 3 months that was refractory to at least two treatments with traditional therapies were eligible for this study. Genital warts were confirmed histologicaliy by biopsy of affected tissue; patients with evidence of mafignant degeneration were excluded. Patients must have been in good health, excluding condylomata, as determined by a preentry history and physical examination. Patients with major immunodeficiencies or those who had received parenteral or oral steroids, radiotherapy, or immunosuppressive medications within 3 months of study entry were excluded. Laboratory screening tests performed before entry included complete blood cell count with differential and platelets, electrolytes, liver function tests, and urinalysis. Patients with abnormal results were excluded from the study. No patient with a positive human immunodeficiency virus antibody screen by enzyme-linked irnmunosorbont assay and confirmatory neutralizing antibody test was entered in the study. Fasting serum lipids were drawn before entry. If the cholesterol or triglyceride levels were greater than 300 mg/dl on two occasions, the patient was not enrolled. Lateral spine x-ray films were done at baseline to rule out changes that could be radiologicaUy confused with any subsequent retinoidrelated changes. Protocol. Patients who met entry criteria and provided signed, informed consent were enrolled in the study. Patients were assigned by a computer-generatedrandom code to one of two treatment groups (Fig. 1). One group of patients received interferon alfa-nl subcutaneously at a dosage of 5 million units daily for 2 weeks, then three times per week for an additional 4 weeks. The other
Volume20 Number 6 June 1989
Interferon alfa-nl and isotretinoin in the treatment of condylomata acuminata 1025
Table I. Demographic characteristics of patients with condylomata acuminata treated with interferon alfa-nl and/or isotretinoin
Treatment group InterferOn(n = 9)alfa'nl [ Age (yr): Mean (range) Race Disease duration (yr) Mean, median (yr) Location of warts Penile Perirectal Both
lsotretinoin (n = 8)
33.4 (19-55) White 6; black, 3 0.25-20 3.6, 1.4
27.6 (20-35) White, 6; black, 1; Oriental, 1 0.33-5 1.5, 0.79
4 4 1
4 2 2
group received isotretinoin (Accutane) at a dosage of 1 mg/kg daily by mouth. At the end of the 6-week treatment period, response was assessed by bidimensional measurements of lesions. Those judged to be 100% clear of visible condylomata were considered to have a complete response (CR). Those with >__50%clearing of condylomata were considered partial responders (PR), and those with >__25%but less than 50% clearing were considered minimal responders (MR). Those with <25% clearing of lesion area were considered nonresponders (NR). Patients initially treated with interferon alfa-nl, who showed less than a complete response after 6 weeks, were offered an additional 6 weeks of interferon, 5 million units three times weekly, plus I mg/kg isotretinoin daily. Patients who showed less than a complete response after 6 weeks of isotretinoixt alone were switched to interferon alfa-nl, 5 million units three times per week for 6 weeks. All patients were then observed for an additional 12 weeks after completion of drug therapy. Patients who had a complete response at the end of the initial 6 weeks of treatment continued without medication and were observed for an additional 18 weeks. Patients who never completely cleared of disease or who relapsed by the end of week 24 of the study were offered the option of additional treatment with interferon alfa-ni, 5 million units subcutaneously three times per week, plus isotretinoin, 1 mg/kg by mouth daily, for a maximum of 12 weeks. Assessment of efllcaey. Patients returned at 2-week intervals during the active drug treatment periods and monthly during the observation periods. Lesions were mapped, and bidimensiona[ measurements of anatomically localized condylomata were recorded at each visit. Standardized photographs were taken at each evaluation to confirm disease assessments. Assessment of safety. Baseline laboratory tests, excluding human immunodeficiency virus antibody,
were repeated every 2 weeks during active drug treatment and at the end of the observation periods. Lateral spine x-ray studies were repeated at study completion. Statistical analysis. Total lesion areas were computed for each patient and then summarized by evaluation week. The difference in percentage change from baseline at week 6 was compared for the primary treatment groups (i.e., interferon alfa-nl vs isotretinoin). Differences between groups were assessed with the use of Wilcoxon's rank sum test. RESULTS Efficacy Twenty-one men with histologieaUy confirmed condylomata acurninata refractory to standard treatment entered the study. Ages ranged from 19 to 55 years (mean, 30.4 years). Fifteen men were white, five were black, and one was Oriental. The duration of genital warts ranged from 3 months to 20 years. Prior treatment included podophyUin in 20 patients, liquid nitrogen in 7 patients, surgery or laser in 2 patients each, electrodesiccation in 3 patients, and triehloroacetic acid in 1 patient. Four patients did not complete primary therapy. One patient initially randomized to interferon alfa-nl therapy had elevated triglycerides at entry and on repeat testing, and he was withdrawn from the study. A second patient receiving interferon alfa-nl declined therapy after 2 weeks because of symptomatic side effects. One patient who was taking isotretinoin alone was lost to follow-up after 2 weeks, and another patient dropped out after 4 weeks because of symptomatic side effects. Seventeen men who completed 6 weeks of the study were evaluated for safety and efficacy. Nine initially were randomized to interferon alfa-nl and
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Table II. Responses of patients treated with interferon alfa-nl followed by combination therapy Percentage change from baseline surface area of
eondylmnata Crossover to I inlerferon and
Disease Patient
duration
No. 1 2 3 4 5 6 7 8 9
P,
19 33 43 44 34 25 21 25 55
Race
(yr)
Location
Interferon
isotretinoin
W B B W W W W W B
0.5 4.9 1.4 2.0 0.7 0.8 0.3 2.4 20.5
P P,PR PR PR PR PR P P P
44.4 18.3 60.5 50 47.5 55.9 55.8 100 33
69.1 -70.4 67.6 98.4 64.7 98.9 ---
12 wk observation
End of
79.2 -69.1 0 95.1 100 97.1 82.1
Penile;PR, perirectal.
Table III. Response of patients treated sequentially with isotretinoin and interferon alfa-nl
i Patient
No. 10 11 12 13 14 15 16 17
PR,
Age
(yr)
Race
34 21 35 24 28 31 24 23
B W W W W W W O
l'ercentagechangefromImsiline surface area of condylomala Crossover End of 12 wk
Disease duration
(yr)
Location
1.1 0.9 2.1 0.3 0.4 5.2 0.6 0.7
PR P,PR P P PR P P P,PR
lsotretinoin
interferon
observation
20.7 17.1 6.9 3.5 Increase 9.1 Increase Increase
84.8 56.2 -Increase Increase 36.4 Increase Increase
99.4 97.2 ---6.5 --
Perireetal;1", penile.
eight to isotretinoin. Demographic characteristics of each group are shown in Table I. Tables II and III list the patients initially assigned to interferon alfa-nl or isotretinoin therapy, respectively. The data from these patients were used for statistical comparisons as already outlined. The interferon alfa-nl group had a mean reduction from baseline of 52% (range, 18.3%-100%), and the isotretinoin group had a mean increase from baseline of 10.9% (range, -20.7~ These mean values were significantly different ( p = 0.0009). The results indicate that interferon alfa-nl was more effective than isotretinoin in reducing the total lesion area at week 6. Nine patients completed 6 weeks of interferon alfa-nl alone (Table II). One patient showed complete response, four were partial responders, three
were minimal responders, and one showed no response. All patients showed some degree of clinical improvement during the course of interferon a|fa-nl. After initial interferon affa-nl therapy the four partial responders and two of the three minimal responders were switched to combination therapy with interferon plus isotretinoin. At the end of an additional 6 weeks of combined therapy, alI six had further regression of warts, with responses ranging from 64.7% to 98.9% clearing from baseline (Fig. 2). Two of these patients, who initially had partial responses, required discontinuation of interferon alfa-nl during the combination treatment period because of elevated liver function test results. These two men were treated with isotretinoin alone for 4 or 5 weeks. Both showed continued improvement on the single agent. Isotretinoin was
Volume 20 Number 6 June 1989
Interferon alfa-nl and isotretinoin in the treatment of condylomata acuminata 1027
Fig. 2. A, Baseline condylolnata patient 7. B, End of 6 weeks' therapy with interferon alfa-nl. C, End of 6 additional weeks' therapy with interferon alfa-nl plus isotretinoin.
discontinued in two patients because of elevated liver function test results after 2 or 5 weeks of combination therapy. Both patients showed continued improvement with interferon alfa-nl alone. Seven patients were evaluated at the completion of 12 or more weeks of observation after drug discontinuation; two patients had continued regression of genital warts. Four had some regrowth of lesions, but these patients still had 69.1% to 97. 1% decrease in lesion surface area from baseline. Only one patient had complete regrowth of his disease. Table III lists the eight patients treated with isotretinoin alone during the 6 weeks of primary therapy. All were nonresponders. In fact, three patients receiving isotretinoin aione had an increase in lesion area during the 6-week period. The patients with progressive disease and four of the five nonresponders taking isotretinoin alone were switched to interferon alfa-nl alone. At the end of the sequential 6 weeks of interferon alfa-nl therapy, there were two patients with a PR, one patient with minimal response, and four nonresponders. At the completion of 12 weeks of observation without drug therapy, the two patients with partial response had continued, but not complete, clearing (97.2%-99.4% of baseline lesion areas) (Fig. 3, A-C).
Only 3 patients completed an additional 6 weeks in the addendum study in which they received combination therapy. Of those, one patient had a complete response, one patient had slight improvement response, and one patient showed no response.
Safety The known biologic side effects were common and generally predictable for each individual drug. Eight of the nine patients initially receiving interferon alfa-nl and 6 of 7 who were switched from isotretinoin to interferon alfa-nl alone had flulike symptoms (fever, chills, and/or malaise) during initiation of therapy. These side effects tended to dissipate during the first few days. Fifteen of 16 patients who received interferon als as a single agent had headache, and 7 patients had gastrointestinal symptoms (nausea, anorexia, and/or diarrhea). These were generally less severe with a three-times-weekly dosing rather than daily administration. All but one of the patients on an interferon alfa-nl regimen experienced fatigue that persisted throughout treatment, although to a lesser degree on the three-times-weekly schedule. Two patients complained of decreased libido, two of increased irritability, and another had an episode of bizarre behavior at a church revival meeting; only
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Fig. 3. A, Patient 10. Baseline condylomata. B, 12 weeks of therapy (isotretinoin followed by 6 weeks of interferon alfa-nl). C, 3 months after treatment. the latter reaction necessitated the patient's dismissal from the study. One patient had seizures during the addendum study as a result of aseptic meningitis of viral origin. Three patients complained of irritation at the wart site while taking interferon alfa-nl alone. Three patients who began the study with interferon alfa-nl therapy alone and two who were switched to interferon alfa-nl alone showed elevated liver function tests results of more than 1.5 times the normal range. These abnormalities resolved when the dosage of interferon alfa-nl was lowered or discontinued. A mild decrease in white blood cell count was noted in most patients on the interferon alfa-nl regimen, but no clinical complications resulted from these changes. All side effects related to interferon alfa-nl therapy were reversible when the drug was discontinued. All patients who took isotretinoin alone experienced dry skin, dry eyes, and/or cheilitis. Four patients complained of wart irritation, three patients complained of fatigue, two patients noted hair thinning, and one patient complained of joint aches. Three patients had elevation of triglycerides greater than two times baseline. Fatigue and/or malaise were the most common side effects reported by patients originally on an interferon alfa-nl regimen alone who were switched to a combination of interferon alfa-nl and isotretinoin therapy. These effects appeared to be additive. There were no increases in triglyceride nor cholesterol levels dur-
ing the combination therapy from that seen with isotretinoin alone. Liver function test results of three patients receiving the combination were more than 1.5 times the normal limits. One patient's values returned to normal limits when interferon alfa-nl was discontinued, and the other two patients' values returned to normal limits when isotretinoin was discontinued. In general, combination therapy of interferon alfa-nl and isotretinoin was well tolerated. DISCUSSION This study confirms the etlicacy of interferon alfa-nl in treating recalcitrant condylomata acuminata in men. Five of 9 men (56%) treated with 5 million units interferon alfa-nl daily for 2 weeks and then three times weekly for 4 weeks had an objective clinical response (>50% clearance of baseline lesion area). None of the patients treated with isotretinoin alone had an objective response. Comparison of mean percentage changes from baseline lesion areas demonstrated a statistically significant difference between these two groups (p = 0.0009). Two of the 7 patients who were switched from isotretinoin to interferon alfa-nl therapy alone for 6 weeks had objective responses. Previous nonplacebo-controlled studies in both men and women with recalcitrant condylomata acuminata that used an identical dosing schedule,
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Interferon alfa-nl and isotretinoin in the treatment of eondylomata aeuminata 1029
but varying doses of interferon alfa-nl have shown similar efficacy. In studies using 1, 3, or 5 million units/m 2, objective responses of 79%, I~ 90%, ~~and 93.8%, 1~ respectively, have been reported. In this study the complete response rate was one of nine patients (11%) receiving interferon alone versus the 21% to 40% reported in these other studies. Patients treated in the current trial did not have any apparent differences in overall tumor mass, duration of disease, and age compared with the other study populations. However, all subjects in the current study were men versus 84% to 100% female subjects in the earlier studies.~~ ~ We earlier reported ~5a similar disparity in response by sex in a study comparing interferon alfa-nl therapy alone versus interferon plus ibuprofen therapy for recalcitrant genital warts. In that study 68% of the women versus 22% of the men had an objective response. An explanation for the sex difference in response to interferon remains unclear. Douglas et al) 6 reported that the presence of antibody to human immunodeficiency virus correlated significantly with a negative response to intralesional interferon alfa-2b treatments in patients with condyloma. We specifically addressed this potential bias inasmuch as all of our patients were human immunodeficiency virusantibody negative. W e chose to evaluate the possible synergistic effect of retinoids with interferon because of isolated reports of their efficacy in various human papillomavirus-related tumors) 7-2~ Two immunocompromised patients with widespread and debilitating "common" w a r t s 17,18 and five patients with epidermodysplasia verruciformis had marked improvement with etretinate therapy) 9,2~ In addition, isotretinoin was used in five patients with juvenile laryngeal papillomatosis, with a complete response in two patients and a partial response in one patient. 21 The hallmark of human papillomavirus infection is epithelial hyperplasia, 22 and retinoids have an endogenous antiproliferative effect through control of epithelial cell differentiation? 3 Retinoids also have an immunomodulatory effect that we believed may have been of particular benefit in patients with recalcitrant human papillomavirus-related tumors and could complement the same effect seen with interferons. 24 N o patient in this study receiving isotretinoin therapy alone had an objective response. Of the seven patients switched to an interferon alfa-nl
regimen alone after an initial 6 weeks of isotretinoin, only two had an objective response. This is a less favorable response than interferon alfa-nl therapy alone from the outset. An improvement, however, was seen in those men treated with a combination of isotretinoin and interferon alfa-nl for 6 weeks after an initial 6 weeks of interferon alfa-nl alone; their objective response rate increased to 5 of 6 and all had increased clearance. This may be related either to the addition of isotretinoin or to prolonged treatment (12 weeks vs 6 weeks) with interferon alfa-nl. Two large placebo-controlled studies have been published on the intralesional use of interferon alfa-2b. Vance et al. 4 injected 106 or 105 units of interferon alfa-2b or placebo into individual warts three times per week for 3 weeks. At the end of the treatment period no significant difference in response to treatment was seen among the three groups. However, after 9 weeks of posttherapy follow-up, the complete response was 53%, 19%, and 14% in the 106 units interferon, 105 units interferon, and placebo groups, respectively. This study established a threshold interferon level for effective treatment and showed that the improvement may be maximized several weeks after drug discontinuation versus immediately after completion of treatment. Eron et al: conducted a large, placebo-controlled study with the use of 1 million units three times per week for 3 weeks interlesionally and found in the active drug group a 20% complete response rate at week 4 versus a 36% rate at week 16 (13 weeks off the treatment regimen). At this dosage no effect was seen on untreated warts and few side effects were reported, thus making a systemic effect of interferon unlikely:.5 Local injection of a limited number of genital warts may be a reasonable approach to treatment. However, use of interferon in this manner for patients with a large number of warts may be difficult. The total volume of interferon needed to treat many warts effectively probably would result in systemic side effects. In addition, multiple individual injections into genital warts are painful, time-consuming, and expensive. Parenteral treatment with interferon alfa-nl for refractory condylomata acuminata is associated with side effects but, generally, these are well tolerated by patients and dissipate with repeated injections. Patients also are able to administer intramuscular or subcutaneous injections at home, eliminating frequent office
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Journal of the American Academy of Dermatology
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visits. Most important, systemic interferon alfa-nl therapy may result in significant amelioration or complete clearing of condylomata in patients with persistent and/or locally debilitating disease for which other forms of treatment have been unsuccessful. REFERENCES 1. Gissman L, DeVilliers EM, ZurHansen H. Analysis of human genital warts (condylomata acuminata) and other genital tumors for human papillomavirus type 6 DNA. Int J Cancer 1982;29:143-6. 2. Ferenczy A, Mitao M, Nagai N, Silverstein S J, Crum CP. Latent papillomavirus and recurring genital warts. N Engl J Med 1985;313:784-8. 3. Ringenberg QS, Anderson PC. Interferons in the treatment of skin disease. Int J Dermatol 1986;25:273-9. 4. Vance JC, Bart BJ, Hansen RC, et al. Intralesional recombinant alpha-2 interferon for the treatment of patients with eondyloma acuminatum or verruca plantaris. Arch Dermatol 1986;122:272-7. 5. Eron LJ, Judson F, Tucker S, et al. Interferon therapy for condylomata acuminata. N Engl J Med 1986;315:105964. 6. Gibson JR. Intralesional human lymphoblastoid interferon alpha for the treatment of cutaneous, nongenitaI viral warts. Arch Dermatol 1986;122:1098-9. 7. Gibson JR, Harvey SG. Interferon in the treatment of persistent viral warts. Dermatologica 1984;169:47-8. 8. Berman B, Davis-Reed L, Silverstein L, et al. Treatment of verrucae vulgaris with alpha-2 interferon. J Infect Dis 1986;154:328-30. 9. Geffen JR, Klein R J, Friedman-Kien AE. Intralesional administration of large doses of human leukocyte interferon for the treatment of condylomata acuminata. J Infect Dis 1984;150:612-5. 10. Gall SA, Hughes CE, Trofatter K. Interferon for the therapy of condyloma acuminatum. Am J Obstet Gynecol 1985;153:157-63. 11. Gall SA, Hughes CE, Mounts P, Segriti A, Weck PK, Whisnant JK. Efficacy of human lymphoblastoid interferon in the therapy of resistant condyloma acuminata. Obstet Gynecol 1986;67:643-51. 12. Gross G, Roussaki A, Schopf E, De Villiers EM, Papendick U. Successful treatment of condylomata acuminata and Bowenoid papulosis with subcutaneous injections of
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low-dose recombinant alpha interferon. Arch Dermatol 1986;122:749-50. Androphy El, Dvoretzky I, Maluish A_E, Wallace HJ, Lowy DR. Response of warts in epidermodysplasia verruciformis to treatment with systemic and intralesional alpha interferon. J AM ACA~ DaRMATOL 1984;11:197202. Gross G, Ikenberg H, Roussaki A, Drees N, Schopf E. Systemic treatment of condylomata acuminata with recombinant interferon-alpha-2a: low-dose superior to the high-dose regimen. Chemotherapy 1986;32:537-41. Olsen EA, Trofatter KF, Gall SA, et al. Human lymphoblastoid alpha-interferon in the treatment of refractory condyloma acuminata. J Invest Dermatol 1985;84:359. Douglas Jr JM, Rogers M, Judson FN. The effect of asymptomatic infection with HTLV-III on the response of anogenital warts to intralesional treatment with recombinant alpha 2 interferon. J Infect Dis 1986;154:331-4. Gross G, Pfister H, Hagedorn M, Stahn R. Effect of oral aromatic retinoid (Ro 10-9359) on human papilloma virus-2-induced common warts. Dermatologica 1983; 166:48-53. Boyle J, Dick DC, Mackie RM. Treatment of extensive virus warts with etretinate (Tegison) in a patient with sarcoidosis. Clin Exp Dermatol 1983;8:33-6. Jablonska S, Obalek S, Wolska H, Jarzabek-Chorzelska M. Ro 10-9359 in epidermodysplasia verruciformis. Preliminary report. In: Orfanos CE, Braun-Falco O, Farber EM, Grupper Ch, Polano MK, Schuppli R. Retinoids, advances in basic research and therapy. Berlin: SpringerVerlag, 1981:401-5. Lutzner MA. Oral retinoid treatment of human papillomavirus type 5-induced epidermodysplasia verruciformis. N Engl J Med 1981;302:1091. Alberts DS, Coulthard SW, Meyskens FL. Regression of aggressive laryngeal papillomatosis with 13-cis-retinoic acid (Accutane). J Biol Response Mod 1986;5:124-8. Lutzner MA. The human papillomaviruses. Arch Dermatol 1983;119:631-5. Spore MB. Retinoids: new developments in their mechanism of action as related to control of proliferative diseases. In: Orfanos CE, Braun-Falco O, Farber EM, Grupper Ch, Polano MK, Schuppli R, eds. Retinoids, Advances in Basic Research and Therapy. Berlin: Springer-Verlag, 1981:401-5. Borden EC, Ball LA. Interferons: biochemical, cell growth inhibitory, and immunological effects. Prog Hematol 1981;12:299-339.