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A Guide to Immunotherapy of Genital Warts

Focus on Interferon and Imiquimod

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Abstract

Genital warts affect at least 1% of sexually active adults. Current therapies are inadequate because they are often painful, may fail to prevent recurrence and transmission of warts, and usually require either surgery or at least application by a physician. Investigation of immunotherapy for genital warts began with interferon. It has been studied in topical, intralesional, systemic and adjuvant applications. We review the major clinical trials of interferon for genital warts, and conclude that intralesional therapy with interferon-α or interferon-β, with complete response rates of 36 to 63%, is the most successful route for interferon monotherapy. In choosing patients for therapy with interferon, major considerations include immune status, pregnancy and ability to return for frequent injections.

Imiquimod is a new immune response enhancer that acts through stimulating host cytokine production. Interleukins-1, -2, -6, -8 and -12, interferons α, β and γ and tumour necrosis factor α have all been associated with the mechanism of action of imiquimod. Recently, 3 clinical trials have reported positive results using topical imiquimod to treat genital warts. Complete response rates ranged from 37 to 54% for these controlled trials of 5% imiquimod cream. Adverse effects reported include localised pruritis, erythema, erosion, burning and pain, which were rarely severe enough to cause discontinuation of the medication. Although further trials are necessary to identify the role of imiquimod in the therapy of genital warts, it appears to be an efficacious and well tolerated patient-controlled measure for wart therapy.

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References

  1. Koutsky LA, Galloway DA, Holmes KK. Epidemiology of genital human papillomavirus infection. Epidemiol Rev 1988; 10: 122–63

    PubMed  CAS  Google Scholar 

  2. Centers for Disease Control, Atlanta. Annual report of division of STD/HIV prevention. 1991; 13: 161–3

    Google Scholar 

  3. Chuang TY. Condyloma acuminata (genital warts). An epidemiologic view. J Am Acad Dermatol 1987; 16: 376–84

    Article  PubMed  CAS  Google Scholar 

  4. Koutsky, L. Epidemiology of genital human papillomavirus infection. Am J Med 1997; 102(5A): 3–8

    Article  PubMed  CAS  Google Scholar 

  5. Munk C, Svare EI, Poll P, et al. History of genital warts in 10,838 women 20 to 29 years of age from the general population. Sex Transm Dis 1997; 24(10): 567–72

    Article  PubMed  CAS  Google Scholar 

  6. Jonsson M, Karlsson R, Rylander E, et al. The associations between risk behavior and reported history of sexually transmitted diseases among young women: a population based study. Int J STD ADS 1997; 8: 501–5

    Article  CAS  Google Scholar 

  7. Oriel JD. Natural history of genital warts. Br J Vener Dis 1971; 47: 1–13

    PubMed  CAS  Google Scholar 

  8. Handsfield HH. Clinical presentation and natural course of anogenital warts. Am J Med 1997; 102(5A): 16–20

    Article  PubMed  CAS  Google Scholar 

  9. Beckman AM, Daling JR, Sherman KJ, et al. Human papillomavirus infection and anal cancer. Int J Cancer 1989; 43: 1042–9

    Article  Google Scholar 

  10. Beutner KR, Tyring SK. Human papillomavirus and human disease. Am J Med 1997; 102(5A): 9–15

    Article  PubMed  CAS  Google Scholar 

  11. Sykes N. Condyoma acuminatum. Int J Dermatol 1995; 35(5): 297–302

    Article  Google Scholar 

  12. Consensus Development Conference on Diagnosis and Management of External Genital Warts. Chicago (IL): American Medical Association, 1997

  13. Lorincz AT, Reid R, Jenson AB, et al. Human papillomavirus infection of the cervix: relative risk associations of 15 common anogenital types. Obstet Gynecol 1992; 79: 328–37

    Article  PubMed  CAS  Google Scholar 

  14. Gissmann L. Immunologic responses to human papillomavirus infection. Obstet Gynecol Clin North Am 1996; 23(3): 625–39

    PubMed  CAS  Google Scholar 

  15. Beutner KR, Ferenczy A. Therapeutic approaches to genital warts. Am J Med 1997; 102(5A): 28–37

    Article  PubMed  CAS  Google Scholar 

  16. Wiltz OH, Torregrosa M, Wiltz O. Autogenous vaccine: the best therapy for perianal condylomata acuminata? Dis Colon Rectum 1995; 38: 838–41

    Article  PubMed  CAS  Google Scholar 

  17. Coleman N, Birley HDL, Renton AM, et al. Immunological events in regressing genital warts. Am J Clin Pathol 1994; 102: 768–74

    PubMed  CAS  Google Scholar 

  18. Isaacs A, Lindemann J. Virus interference I: the interferon. Proc R Soc Ser B 1957; 147: 258–67

    Article  CAS  Google Scholar 

  19. Rockley PF, Tyring SK. Interferons alpha, beta, and gamma therapy of anogenital human papillomavirus infections. Pharmacol Ther 1995; 65(2): 265–87

    Article  PubMed  CAS  Google Scholar 

  20. Nash T. Immunity to viruses. In: Roitt I, Brostoff J, Male D, editors. Immunology. 4th ed. Barcelona: Mosby, 1996: 16.1–8

    Google Scholar 

  21. Rusconi S, Agarossi A, Ravasi L, et al. Serum 2′-5′- oligoadenylate synthetase levels and clinical response to interferon-beta therapy in women with genital human papillomavirus infection. J Infect Dis 1994; 169: 1112–5

    Article  PubMed  CAS  Google Scholar 

  22. Grassegger A, Rollinger-Holzinger I, Zeiger BWH, et al. Spontaneous or interferon-gamma-induced T-cell infiltration, HLA-DR and ICAM-1 expression in genitoanal warts are associated with TH1 or mixed TH1/TH2 cytokine mRNA expression profiles. Arch Dermatol Res 1997; 289: 243–50

    Article  PubMed  CAS  Google Scholar 

  23. Arany I, Tyring SK. Activation of local cell-mediated immunity in interferon-responsive patients with human papillomavirus-associated lesions. J Interferon Cytokine Res 1996; 16: 453–60

    Article  PubMed  CAS  Google Scholar 

  24. Turek LP, Byrne JC, Lowy DR, et al. Interferon induces morphologic reversion with elimination of extrachromosomal viral genomes in bovine papillomavirus-transformed mouse cells. Proc Natl Acad Sci U S A 1982; 79: 7914–8

    Article  PubMed  CAS  Google Scholar 

  25. Finter NB. An overview of Wellferon (interferon alpha-n1): the product. Med Clin North Am 1986; 70 Suppl.: 13–8

    Google Scholar 

  26. Petska S. The human interferons — from protein purification and sequence to cloning and expression in bacteria: before, between and beyond. Arch Biochem Biophys 1983; 221: 1–37

    Article  Google Scholar 

  27. Vesterinen E, Meyer B, Cantell K, et al. Treatment of vaginal flat condyloma with interferon cream. Lancet 1984; I: 157

    Article  Google Scholar 

  28. Keay S, Teng N, Eisenberg M, et al. Topical interferon for treating condyloma acuminata in women. J Infect Dis 1988; 158: 934–9

    Article  PubMed  CAS  Google Scholar 

  29. Syed TA, Lundin S, Cheema KM, et al. Human leukocyte interferon alpha in cream, for the treatment of genital warts in Asian women: a placebo-controlled double-blind study. Clin Invest 1994; 72: 870–3

    Article  CAS  Google Scholar 

  30. Syed TA, Cheema KM, Khayyami M, et al. Human leukocyte interferon-alpha versus podophyllotoxin in cream for the treatment of genital warts in males: a placebo-controlled double-blind comparative study. Dermatology 1995; 191: 129–32

    Article  PubMed  CAS  Google Scholar 

  31. Syed TA, Khayyami M, Kriz D, et al. Management of genital warts in women with human leukocyte interferon-alpha versus podophyllotoxin in cream: a placebo-controlled, double- blind comparative study. J Mol Med 1995; 73: 255–8

    PubMed  CAS  Google Scholar 

  32. Vance JC, Bart BJ, Hansen RC, et al. Intralesional recombinant alpha-2 interferon for the treatment of patients with condyloma acuminatum-verruca plantaris. Arch Dermatol 1986; 122: 272–7

    Article  PubMed  CAS  Google Scholar 

  33. Eron L, Judson F, Tucker S, et al. Interferon therapy for condyloma acuminata. N Engl J Med 1986; 315: 1059–64

    Article  PubMed  CAS  Google Scholar 

  34. Friedman-Kien AE, Eron LJ, Conant M, et al. Natural interferon-alpha for treatment of condylomata acuminata. JAMA 1988; 259: 533–8

    Article  PubMed  CAS  Google Scholar 

  35. Welander CE, Homesley, HD, et al. Intralesional interferon alfa- 2b for the treatment of genital warts. Am J Obstet Gynecol 1990; 162: 348–54

    PubMed  CAS  Google Scholar 

  36. Friedman-Kien AE. Management of condyloma acuminata with Alferon N injection, interferon alpha-n3 (human leukocyte derived). Am J Obstet Gynecol 1995; 172 (4 Pt 2): 1359–68

    Article  PubMed  CAS  Google Scholar 

  37. Reichman RC, Oakes D, Bonnez W, et al. Treatment of condyloma acuminatum with three different interferons administered intralesionally: a double-blind, placebo-controlled trial. Ann Intern Med 1988; 108: 675–9

    PubMed  CAS  Google Scholar 

  38. Monsonego J, Cessot G, Ince SE, et al. Randomised double-blind trial of recombinant interferon-beta for condyloma acuminatum. Genitourin Med 1996; 72: 111–4

    PubMed  CAS  Google Scholar 

  39. Bornstein J, Pascal B, Zarfati D, et al. Recombinant human interferon-beta for condyloma acuminata: a randomized, double-blind, placebo-controlled study of intralesional therapy. Int J STD AIDS 1997; 8: 614–21

    Article  PubMed  CAS  Google Scholar 

  40. Reichman RC, Oakes D, Bonnez W, et al. Treatment of condyloma acuminatum with three different interferon-alpha preparations administered parenterally: a double-blind, placebo- controlled trial. J Infect Dis 1990; 162: 1270–6

    Article  PubMed  CAS  Google Scholar 

  41. Condylomata International Collaborative Study Group. Recurrent condylomata acuminata treated with recombinant interferon-alpha-2a. JAMA 1991; 265: 2684–7

    Article  Google Scholar 

  42. Condylomata International Collaborative Study Group. A comparison of interferon alfa-2a and podophyllin in the treatment of primary condyloma acuminata. Genitourin Med 1991; 67: 394–9

    Google Scholar 

  43. Condylomata International Collaborative Study Group. Recurrent condylomata acuminata treated with recombinant interferon-alpha-2a. Acta Derm Venereol 1993; 73: 223–6

    Google Scholar 

  44. Schonfeld A, Nitke S, Schattner A, et al. Intramuscular human interferon-beta injections in treatment of condyloma acuminata. Lancet 1984; I: 1038–42

    Article  Google Scholar 

  45. Olmos L, Vilata J, Ridriguez Pichardo A, et al. Double-blind, randomized clinical trial on the effect of interferon-beta in the treatment of condyloma acuminata. Int J STD AIDS 1994; 5(3): 182–5

    PubMed  CAS  Google Scholar 

  46. Condylomata International Collaborative Study Group. Randomized placebo-controlled double-blind combined therapy with laser surgery and systemic IFN-alpha 2a in the treatment of anogenital condylomata acuminatum. J Infect Dis 1993; 167: 824–9

    Article  Google Scholar 

  47. Nieminen P, Markku A, Lehtinen M, et al. Treatment of genital HPV infection with carbon dioxide laser and systemic interferon alpha-2b. Sex Transm Dis 1994; 21(2): 65–9

    Article  PubMed  CAS  Google Scholar 

  48. Handley JM, Horner T, Maw RD, et al. Subcutaneous interferon alpha-2a combined with cryotherapy versus cryotherapy alone in the treatment of primary anogenital warts: a randomized observer blind placebo-controlled study. Genitourin Med 1991; 67: 297–302

    PubMed  CAS  Google Scholar 

  49. Eron LJ, Alder MB, O’Rourke JM, et al. Recurrence of condyloma acuminata following cryotherapy is not prevented by systemically administered interferon. Genitourin Med 1993; 69: 91–3

    PubMed  CAS  Google Scholar 

  50. Bonnez W, Oakes D, Bailey-Farchione A, et al. A randomized, double-blind, placebo-controlled trial of systemically administered interferon-alpha, -beta, or -gamma in combination with cryotherapy for the treatment of condyloma acuminatum. J Infect Dis 1995; 171: 1081–9

    Article  PubMed  CAS  Google Scholar 

  51. Douglas JM, Eron LJ, Judson FN, et al. A randomized trial of combination therapy with intralesional interferon alpha-2b and podophyllin versus podophyllin alone for the therapy of anogenital warts. J Infect Dis 1990; 162: 52–9

    Article  PubMed  Google Scholar 

  52. Armstrong DKB, Maw RD, Dinsmore WW, et al. A randomized, double-blind, parallel group study to compare subcutaneous interferon alpha-2a plus podophyllin with placebo plus podophyllin in the treatment of primary condyloma acuminata. Genitourin Med 1994; 70: 389–93

    PubMed  CAS  Google Scholar 

  53. Armstrong DKB, Maw RD, Dinsmore WW, et al. Combined therapy trial with interferon alpha-2a and ablative therapy in the treatment of anogenital warts. Genitourin Med 1996; 72: 103–7

    PubMed  CAS  Google Scholar 

  54. Cirelli R, Tyring SK. Interferons in human papillomavirus infections. Antiviral Res 1994; 24: 191–204

    Article  PubMed  CAS  Google Scholar 

  55. Geffen JR, Klein RJ, Friedman-Kien AE. Intralesional administration of large doses of human leukocyte interferon for the treatment of condyloma acuminata. J Infect Dis 1984; 150: 612–5

    Article  PubMed  CAS  Google Scholar 

  56. Vance JC, Bart BJ, Bart B, et al. Effectiveness of intralesional human recombinant alpha-2b interferon (Intron-A) for the treatment of patients with condyloma acuminatum. Clin Res 1986; 34: 993A

    Google Scholar 

  57. Boot JM, Blog B, Stolz E. Intralesional interferon alpha-2b treatment of condyloma acuminata previously resistant to podophyllum resin application. Genitourin Med 1989; 65: 50–3

    PubMed  CAS  Google Scholar 

  58. Scott GM, Csonka GW Effect of injections of small doses of human fibroblast interferon into genital warts. A pilot study. Br J Vener Dis 1979; 55: 442–5

    PubMed  CAS  Google Scholar 

  59. Marcovici R, Peretz BA, Paldi E. Human fibroblast interferon therapy in patients with condyloma acuminata. Isr J Med Sci 1983; 19: 104

    Google Scholar 

  60. Dinsmore W, Jordan J, O’Mahony C, et al. Recombinant human interferon-beta in the treatment of condyloma acuminata. Int J STD AIDS 1997; 8: 622–8

    Article  PubMed  CAS  Google Scholar 

  61. Kirby P, Wells D, Kiviat N, et al. Aphase I trial of intramuscular recombinant human gamma interferon for refractory genital warts. J Infect Dis 1986; 86: 485

    Google Scholar 

  62. Gross G, Roussaki A, Brzoska J. Low doses of systemically administered recombinant interferon gamma effective in the treatment of genital warts. J Invest Dermatol 1988; 90: 242

    Google Scholar 

  63. Kirby PK, Kiviat N, Beckman A, et al. Tolerance and efficacy of recombinant human gamma interferon in the treatment of refractory genital warts. Am J Med 1988; 85: 183–8

    Article  PubMed  CAS  Google Scholar 

  64. Zouboulis C, Stadler R, Ikenberg H, et al. Short-term systemic recombinant interferon-gamma treatment is ineffective in recalcitrant condyloma acuminata. J Am Acad Dermatol 1991; 24: 302–3

    Article  PubMed  CAS  Google Scholar 

  65. Schneider A, Papendick U, Gissman L, et al. Interferon treatment of human genital papillomavirus infection: importance of viral type. Int J Cancer 1987; 40: 610–4

    Article  PubMed  CAS  Google Scholar 

  66. Fierlbeck G, Rassner G. Treatment of condyloma acuminata with systemically administered recombinant gamma interferon. Z Hautki 1987; 62: 1280–7

    CAS  Google Scholar 

  67. Vance JC, Davis D. Interferon alpha-2b injections used as an adjuvant therapy to carbon dioxide laser vaporization of recalcitrant anogenital condyloma acuminata. J Invest Dermatol 1990; 95: 146S–8S

    Article  PubMed  CAS  Google Scholar 

  68. Hohenleutner U, Landthaler M, Braun-Falco O. Post-operative adjuvante therapie mit interferon-alfa-2b nach laserchirurgie von condylomata acuminata. Hautarzt 1990; 41: 545–8

    PubMed  CAS  Google Scholar 

  69. Erpenbach K, Derschum W, Vietsch HV Adjuvant-systemische interferon-alpha 2b — behandlung bei therapier resistenten anogenitalen condylomata acuminata. Urologe A 1990; 29: 43–5

    PubMed  CAS  Google Scholar 

  70. Peterson CS, Bjerring P, Larsen J, et al. Systemic interferon alpha-2b increases the cure rate in laser-treated patients with multiple persistent genital warts: a placebo-controlled study. Genitourin Med 1991; 67: 99–102

    Google Scholar 

  71. Davis BE, Noble MJ. Initial experience with combined interferon alpha-2b and carbon dioxide laser for the treatment of condyloma acuminata. J Urol 1992; 147: 627–9

    PubMed  CAS  Google Scholar 

  72. Reid R, Greenberg MD, Pizzuti DJ, et al. Superficial laser vulvectomy V Surgical debulking is enhanced by adjuvant systemic interferon. Am J Obstet Gynecol 1992; 166: 815–20

    PubMed  CAS  Google Scholar 

  73. Bernstein DI, Miller RL, Harrison CJ. Adjuvant effects of imiquimod on a herpes simplex virus type 2 glycoprotein vaccine in guinea pigs. J Infect Dis 1993; 167: 731–5

    Article  PubMed  CAS  Google Scholar 

  74. Miller RL, Imbertson LM, Reiter MJ, et al. Inhibition of herpes simplex virus infection in a guinea pig model by S-26308. ASM/Interscience Conference on Antimicrobial Agents and Chemotherapy; 1985 Sep 29–Oct 2; Minneapolis, MN: 235

  75. Harrison CJ, Jenski L, Voychehovski I, et al. Modification of immunological responses and clinical disease during R-837 treatment of genital HSV-2 infection. Antiviral Res 1988; 10: 209–24

    Article  PubMed  CAS  Google Scholar 

  76. Bernstein DI, Harrison CJ. Effects of the immunomodulating agent R-837 on the acute and latent herpes simplex virus type 2 infections. Antimicrob Agents Chemother 1989; 33: 1511–5

    Article  PubMed  CAS  Google Scholar 

  77. Harrison CJ, Stanberry LR, Bernstein DI. Effects of cytokines and R-837, a cytokine inducer, on UV-irradiation augmented recurrent genital herpes in guinea pigs. Antiviral Res 1991; 15: 315–22

    Article  PubMed  CAS  Google Scholar 

  78. Chen M, Griffith BP, Lucia HL, et al. Efficacy of S-26308 against guinea pig cytomegalovirus. Antimicrob Agents Chemother 1988; 32: 678–83

    Article  PubMed  CAS  Google Scholar 

  79. Kende M, Lupton HW, Canonico PG. Treatment of experimental viral infections with immunomodulators. Adv Biosci 1988; 68: 51

    Google Scholar 

  80. Miller RL, Imbertson LM, Reiter MJ, et al. Interferon induction by antiviral S-26308 in guinea pigs. ASM, Interscience Conference on Antimicrobial Agents and Chemotherapy; 1986 Sep 28–Oct 1; New Orleans, LA; 168

  81. Sidky YA, Borden EC, Weeks CE, et al. Inhibition of murine tumor growth by an interferon inducing imidazoquinolone. Cancer Res 1992; 52: 3528–33

    PubMed  CAS  Google Scholar 

  82. Gibson SJ, Elrod SV, Miller RL, et al. Oral R-837 induces alpha interferon in cynomolgus monkeys. J Interferon Res 1990; 10: S124

    Google Scholar 

  83. Reiter MJ, Testerman TL, Miller RL, et al. Cytokine induction in mice by the immunomodulator imiquimod. J Leukoc Biol 1994; 55: 234–40

    PubMed  CAS  Google Scholar 

  84. Wagner TL, Horton VL, Carlson GL, et al. Induction of cytokines in cynomolgus monkeys by the immune response modifiers, imiquimod, S-27609, and S-28463. Cytokine 1997; 9(11): 837–45

    Article  PubMed  CAS  Google Scholar 

  85. Weeks CE, Gibson J. Induction of interferon and other cytokines by imiquimod and its hydroxylated metabolite R- 842 in human blood cells in vitro. J Interferon Res 1993; 14: 93–7

    Google Scholar 

  86. Gibson SJ, Imbertson LM, Wagner TL, et al. Cellular requirements for cytokine production in response to the immunomodulators imiquimod and S-27609. J Interferon Cytokine Res 1995; 15: 537–45

    Article  PubMed  CAS  Google Scholar 

  87. Megyeri K, Au WC, Rosztoczy I, et al. Stimulation of interferon and cytokine gene expression by imiquimod and stimulation by Sendai virus utilize similar signal transduction pathways [published erratum appears in Mol Cell Biol 1995; 15 (5): 2905]. Mol Cell Biol 1995; 15(4): 2207–18

    PubMed  CAS  Google Scholar 

  88. Testerman TL, Gerster JF, Imbertson LM, et al. Cytokine induction by the immunomodulators imiquimod and S-27609. J Leukoc Biol 1995; 58: 365–72

    PubMed  CAS  Google Scholar 

  89. Kono T, Kondo S, Pastore S et al. Effects of a novel topical immunomodulator, imiquimod, on keratinocyte cytokine gene expression. Lymphokine Cytokine Res 1994; 13(2): 71–6

    PubMed  CAS  Google Scholar 

  90. Borden E, Witt P, Kvam D et al. An effective oral inducer of interferons in humans. J Interferon Res 1991; 11: S92

    Google Scholar 

  91. Imbertson LM, Weeks C, Adams N et al. Induction of antiviral activity and cytokines by oral imiquimod in healthy volunteers. J Interferon Res 1992; 12: S127

    Google Scholar 

  92. Arany I, Tyring SK, Stanley MA, et al. Enhancement of the innate and cellular immune response in patients with genital warts treated with topical imiquimod cream 5%. J Infect Dis 1998; 178: 551–5

    Article  PubMed  Google Scholar 

  93. Edwards L, Ferenczy A, Lawrence E, et al. Self-administered topical 5% imiquimod cream for external anogenital warts. Arch Dermatol 1998; 134(1): 25–30

    Article  PubMed  CAS  Google Scholar 

  94. Beutner KR, Spotswood LS, Hougham AJ, et al. Treatment of genital warts with an immune-response modifier (imiquimod). J Am Acad Dermatol 1998; 38: 230–9

    Article  PubMed  CAS  Google Scholar 

  95. Beutner KR, Tyring SK, Trofatter KF, et al. Imiquimod, a patient-applied immune-response modifier for treatment of external genital warts. Antimicrob Agents Chemother 1998; 42(4): 789–94

    PubMed  CAS  Google Scholar 

  96. Greenberg MD, Rutledge LH, Reid R, et al. A double-blind, randomized trial of 0.5% podofilox and placebo for the treatment of genital warts in women. Obstet Gynecol 1991; 77: 735–9

    PubMed  CAS  Google Scholar 

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Czelusta, A.J., Evans, T., Arany, I. et al. A Guide to Immunotherapy of Genital Warts. BioDrugs 11, 319–332 (1999). https://doi.org/10.2165/00063030-199911050-00004

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