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5% Imiquimod Suppositories Decrease the DNA Load of Intra-anal HPV Types 6 and 11 in HIV-Infected Men After Surgical Ablation of Condylomata Acuminata

5% Imiquimod Suppositories Decrease the DNA Load of Intra-anal HPV Types 6 and 11 in HIV-Infected... Human papillomavirus (HPV) infections of the anogenital tract belong to the most common group of sexually transmitted diseases worldwide. So far, more than 90 different HPV types have been isolated from cutaneous and mucosal lesions.1 Mucosal HPV-6 and -11 are the most frequent types found in patients with genital warts or condylomata acuminata (CA).2 In human immunodeficiency virus (HIV)–infected individuals, standard therapies for CA often fail, probably because of the suppressed cellular immune response leading to an insufficient control and increased replication of HPV.3,4 In this context, intra-anal CA in HIV-infected men represents a special therapeutic challenge, as both ablation and follow-up are difficult to perform because of the local anatomical situation. Imiquimod, a topical immune response modifier, has been approved for the treatment of CA in the United States and Europe. In 2002, Kaspari et al5 reported that the use of suppositories containing imiquimod successfully prevented recurrences of intra-anal CA after surgical ablation in HIV-negative men. We report the effects of the use of 5% imiquimod suppositories on HPV-6 and -11 DNA load in the management of CA in HIV-infected men who have sex with men. Methods The protocol for this study was approved by the ethics review board of Ruhr-University Bochum, Bochum, Germany. Seven consecutive HIV-positive men were treated with imiquimod suppositories after surgical ablation (with electrocautery) of intra-anal CA. Lesional biopsy specimens obtained before therapy were consistent with CA and excluded dysplastic changes within the CA. The patients' characteristics are summarized in the Table. Suppositories containing 5% imiquimod were prepared as previously reported5 and were self-applied overnight (starting 4 days after electrocautery) 3 times a week for a total of 16 weeks. All patients included in this trial were instructed to have only condom-protected intercourse during the time of imiquimod application. Proctoscopic examination, cytologic screening (circumferential swabs at the squamocolumnar junction), HPV typing, and HPV load determination were performed every 4 to 8 weeks, as previously described.6,7 The DNA loads of HPV-6 and -11, as well as -16, -18, -31, and -33, were determined by real-time polymerase chain reaction analysis with type-specific primers and probes, with all values being expressed as HPV copies per β-globin gene copy. Table. Patients' Characteristics, Intra-anal HPV Spectrum, and HPV DNA Loads Before and After Imiquimod Therapy* View LargeDownload Results All patients carried HPV-6 or -11 in the intra-anal lesional swabs that were obtained at the start of therapy. Also, a broad spectrum of high- and low-risk HPV types were present (Table). In all patients, the use of imiquimod suppositories led to a sharp decrease in the HPV-6 or -11 DNA load along with a decrease in the DNA load of coinfecting high-risk types 16, 18, 31, and 33. Median low-risk HPV DNA loads (HPV-6 and -11) decreased from 484 (range, 37-6435) in the first samples obtained before surgical ablation to 0.9 (range, 0-74) at the end of therapy and then slightly increased to 10 (range, 0-189) a few months (range, 2-9 months) after the end of therapy. The respective values for median high- risk DNA loads of HPV-16, -18, -31, and -33 were 61 (first sample), 0.1 (end of therapy), and 3 (follow-up). No patient was HPV negative at the end of therapy, but most patients had a decrease in the number of infecting HPV types, and 2 patients became HPV-6 or -11 DNA negative (Table). Other than moderate erythema in all patients and mild erosions in 1 patient (No. 7), no local or systemic adverse effects were observed. Interestingly, none of the patients developed influenzalike symptoms, which we had previously observed in 4 of 28 patients who had been treated with imiquimod for anal intraepithelial neoplasia (U.W., N.H.B., S.J.W., et al, unpublished data, September 2005). However, 3 of those 4 patients had received imiquimod cream and not suppositories. All of our patients with CA were free of disease at the end of therapy, but 3 of 6 patients who were followed up developed recurrent CA 2, 7, and 8 months after the end of therapy. Except for 1 patient (No. 2, who had no recurrrence), all patients received antiretroviral therapy during and after imiquimod therapy. No obvious differences in HIV RNA and CD4 cell counts were observed in patients with or without recurrences. However, 2 of the patients with recurrent CA had Centers for Disease Control and Prevention stage C3 disease (Table). Comment Our findings are in contrast to those of Kaspari et al,5 who did not see recurrences in 10 HIV-negative patients within a mean follow-up time of 9 months. The poorer outcome in our patients can be explained on the one hand by the HIV-associated immunosuppression probably leading to a new increase in HPV-11 DNA load (patient 6). On the other hand, unprotected anal intercourse likely led to the acquisition of the CA-associated HPV types 40 and 42 at the end of therapy in 2 patients (patients 3 and 4; patient 4 also acquired an intra-anal primary syphilis lesion at that time). No patient had developed anal intraepithelial neoplasia or demonstrated cytologic deterioration at their last visit. In contrast, 3 patients with intra-anal high-grade squamous intraepithelial lesions at their first visit had normal or low-grade lesions at the end of therapy and at follow-up visits. This result could be a beneficial effect of the decrease in high-risk HPV DNA loads that were observed, because increased high-risk HPV DNA loads have been associated with cervical intraepithelial neoplasias in HIV-positive women.7 Among immunosuppressed patients with CA, there have been reports of high recurrence rates (66%) after surgical excision and poor clearance rates (11%) with the use of imiquimod alone.4,8 Application of imiquimod suppositories after the surgical removal of intra-anal CA could be a possible treatment option for HIV-positive patients, although controlled clinical trials in a larger collective of patients are needed to confirm our encouraging viral load data and to find out whether relapse rates with the use of imiquimod after surgery are significantly lower than with surgery alone. The concomitant reduction of high-risk HPV DNA loads might also reduce the risk of the development of intra-anal intraepithelial neoplasia. Patients and their partners should be advised to use condoms during and after imiquimod therapy to avoid or diminish new infections with further HPV types and other sexually transmitted pathogens, especially since imiquimod-treated skin might allow easier entry of sexually transmitted diseases owing to skin barrier damage. Back to top Article Information Correspondence: Dr Kreuter, Department of Dermatology, Ruhr-University Bochum, Gudrunstrasse 56, D-44791 Bochum, Germany (a.kreuter@derma.de). Financial Disclosure: None. Funding/Support: This study was supported in part by the German Competence Network HIV/AIDS (Federal Ministry of Education and Research, grant 01KI 0211). References 1. de Villiers EM, Fauquet C, Broker TR, et al. Classification of papillomaviruses. Virology. 2004;324:17-27. PubMedGoogle ScholarCrossref 2. Dupin N. Genital warts. Clin Dermatol. 2004;22:481-486. PubMedGoogle ScholarCrossref 3. Palefsky JM, Holly EA. Chapter 6: immunosupression and co-infection with HIV. J Natl Cancer Inst Monogr. 2003;31:41-46. PubMedGoogle ScholarCrossref 4. De la Fuente SG, Ludwig KA, Mantyh CR. Preoperative immune status determines anal condyloma recurrence after surgical excision. Dis Colon Rectum. 2003;46:367-373. PubMedGoogle ScholarCrossref 5. Kaspari M, Gutzmer R, Kaspari T, Kapp A, Brodersen JP. Application of imiquimod by suppositories (anal tampons) efficiently prevents recurrences after ablation of anal canal condyloma. Br J Dermatol. 2002;147:757-759. PubMedGoogle ScholarCrossref 6. Kreuter A, Brockmeyer NH, Hochdorfer B, et al. Clinical spectrum and virologic characteristics of anal intraepithelial neoplasia in HIV infection. J Am Acad Dermatol. 2005;52:603-608. PubMedGoogle ScholarCrossref 7. Weissenborn SJ, Funke AM, Hellmich M, et al. Oncogenic human papillomavirus DNA loads in human immunodeficiency virus–positive women with high-grade cervical lesions are strongly elevated. J Clin Microbiol. 2003;41:2763-2767. PubMedGoogle ScholarCrossref 8. Gilson RJ, Shupack JL, Friedman-Kien AE, et al. A randomized, controlled, safety study using imiquimod for the topical treatment of anogenital warts in HIV-infected patients. AIDS. 1999;13:2397-2404. PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Dermatology American Medical Association

5% Imiquimod Suppositories Decrease the DNA Load of Intra-anal HPV Types 6 and 11 in HIV-Infected Men After Surgical Ablation of Condylomata Acuminata

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Publisher
American Medical Association
Copyright
Copyright © 2006 American Medical Association. All Rights Reserved.
ISSN
0003-987X
eISSN
1538-3652
DOI
10.1001/archderm.142.2.243
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Abstract

Human papillomavirus (HPV) infections of the anogenital tract belong to the most common group of sexually transmitted diseases worldwide. So far, more than 90 different HPV types have been isolated from cutaneous and mucosal lesions.1 Mucosal HPV-6 and -11 are the most frequent types found in patients with genital warts or condylomata acuminata (CA).2 In human immunodeficiency virus (HIV)–infected individuals, standard therapies for CA often fail, probably because of the suppressed cellular immune response leading to an insufficient control and increased replication of HPV.3,4 In this context, intra-anal CA in HIV-infected men represents a special therapeutic challenge, as both ablation and follow-up are difficult to perform because of the local anatomical situation. Imiquimod, a topical immune response modifier, has been approved for the treatment of CA in the United States and Europe. In 2002, Kaspari et al5 reported that the use of suppositories containing imiquimod successfully prevented recurrences of intra-anal CA after surgical ablation in HIV-negative men. We report the effects of the use of 5% imiquimod suppositories on HPV-6 and -11 DNA load in the management of CA in HIV-infected men who have sex with men. Methods The protocol for this study was approved by the ethics review board of Ruhr-University Bochum, Bochum, Germany. Seven consecutive HIV-positive men were treated with imiquimod suppositories after surgical ablation (with electrocautery) of intra-anal CA. Lesional biopsy specimens obtained before therapy were consistent with CA and excluded dysplastic changes within the CA. The patients' characteristics are summarized in the Table. Suppositories containing 5% imiquimod were prepared as previously reported5 and were self-applied overnight (starting 4 days after electrocautery) 3 times a week for a total of 16 weeks. All patients included in this trial were instructed to have only condom-protected intercourse during the time of imiquimod application. Proctoscopic examination, cytologic screening (circumferential swabs at the squamocolumnar junction), HPV typing, and HPV load determination were performed every 4 to 8 weeks, as previously described.6,7 The DNA loads of HPV-6 and -11, as well as -16, -18, -31, and -33, were determined by real-time polymerase chain reaction analysis with type-specific primers and probes, with all values being expressed as HPV copies per β-globin gene copy. Table. Patients' Characteristics, Intra-anal HPV Spectrum, and HPV DNA Loads Before and After Imiquimod Therapy* View LargeDownload Results All patients carried HPV-6 or -11 in the intra-anal lesional swabs that were obtained at the start of therapy. Also, a broad spectrum of high- and low-risk HPV types were present (Table). In all patients, the use of imiquimod suppositories led to a sharp decrease in the HPV-6 or -11 DNA load along with a decrease in the DNA load of coinfecting high-risk types 16, 18, 31, and 33. Median low-risk HPV DNA loads (HPV-6 and -11) decreased from 484 (range, 37-6435) in the first samples obtained before surgical ablation to 0.9 (range, 0-74) at the end of therapy and then slightly increased to 10 (range, 0-189) a few months (range, 2-9 months) after the end of therapy. The respective values for median high- risk DNA loads of HPV-16, -18, -31, and -33 were 61 (first sample), 0.1 (end of therapy), and 3 (follow-up). No patient was HPV negative at the end of therapy, but most patients had a decrease in the number of infecting HPV types, and 2 patients became HPV-6 or -11 DNA negative (Table). Other than moderate erythema in all patients and mild erosions in 1 patient (No. 7), no local or systemic adverse effects were observed. Interestingly, none of the patients developed influenzalike symptoms, which we had previously observed in 4 of 28 patients who had been treated with imiquimod for anal intraepithelial neoplasia (U.W., N.H.B., S.J.W., et al, unpublished data, September 2005). However, 3 of those 4 patients had received imiquimod cream and not suppositories. All of our patients with CA were free of disease at the end of therapy, but 3 of 6 patients who were followed up developed recurrent CA 2, 7, and 8 months after the end of therapy. Except for 1 patient (No. 2, who had no recurrrence), all patients received antiretroviral therapy during and after imiquimod therapy. No obvious differences in HIV RNA and CD4 cell counts were observed in patients with or without recurrences. However, 2 of the patients with recurrent CA had Centers for Disease Control and Prevention stage C3 disease (Table). Comment Our findings are in contrast to those of Kaspari et al,5 who did not see recurrences in 10 HIV-negative patients within a mean follow-up time of 9 months. The poorer outcome in our patients can be explained on the one hand by the HIV-associated immunosuppression probably leading to a new increase in HPV-11 DNA load (patient 6). On the other hand, unprotected anal intercourse likely led to the acquisition of the CA-associated HPV types 40 and 42 at the end of therapy in 2 patients (patients 3 and 4; patient 4 also acquired an intra-anal primary syphilis lesion at that time). No patient had developed anal intraepithelial neoplasia or demonstrated cytologic deterioration at their last visit. In contrast, 3 patients with intra-anal high-grade squamous intraepithelial lesions at their first visit had normal or low-grade lesions at the end of therapy and at follow-up visits. This result could be a beneficial effect of the decrease in high-risk HPV DNA loads that were observed, because increased high-risk HPV DNA loads have been associated with cervical intraepithelial neoplasias in HIV-positive women.7 Among immunosuppressed patients with CA, there have been reports of high recurrence rates (66%) after surgical excision and poor clearance rates (11%) with the use of imiquimod alone.4,8 Application of imiquimod suppositories after the surgical removal of intra-anal CA could be a possible treatment option for HIV-positive patients, although controlled clinical trials in a larger collective of patients are needed to confirm our encouraging viral load data and to find out whether relapse rates with the use of imiquimod after surgery are significantly lower than with surgery alone. The concomitant reduction of high-risk HPV DNA loads might also reduce the risk of the development of intra-anal intraepithelial neoplasia. Patients and their partners should be advised to use condoms during and after imiquimod therapy to avoid or diminish new infections with further HPV types and other sexually transmitted pathogens, especially since imiquimod-treated skin might allow easier entry of sexually transmitted diseases owing to skin barrier damage. Back to top Article Information Correspondence: Dr Kreuter, Department of Dermatology, Ruhr-University Bochum, Gudrunstrasse 56, D-44791 Bochum, Germany (a.kreuter@derma.de). Financial Disclosure: None. Funding/Support: This study was supported in part by the German Competence Network HIV/AIDS (Federal Ministry of Education and Research, grant 01KI 0211). References 1. de Villiers EM, Fauquet C, Broker TR, et al. Classification of papillomaviruses. Virology. 2004;324:17-27. PubMedGoogle ScholarCrossref 2. Dupin N. Genital warts. Clin Dermatol. 2004;22:481-486. PubMedGoogle ScholarCrossref 3. Palefsky JM, Holly EA. Chapter 6: immunosupression and co-infection with HIV. J Natl Cancer Inst Monogr. 2003;31:41-46. PubMedGoogle ScholarCrossref 4. De la Fuente SG, Ludwig KA, Mantyh CR. Preoperative immune status determines anal condyloma recurrence after surgical excision. Dis Colon Rectum. 2003;46:367-373. PubMedGoogle ScholarCrossref 5. Kaspari M, Gutzmer R, Kaspari T, Kapp A, Brodersen JP. Application of imiquimod by suppositories (anal tampons) efficiently prevents recurrences after ablation of anal canal condyloma. Br J Dermatol. 2002;147:757-759. PubMedGoogle ScholarCrossref 6. Kreuter A, Brockmeyer NH, Hochdorfer B, et al. Clinical spectrum and virologic characteristics of anal intraepithelial neoplasia in HIV infection. J Am Acad Dermatol. 2005;52:603-608. PubMedGoogle ScholarCrossref 7. Weissenborn SJ, Funke AM, Hellmich M, et al. Oncogenic human papillomavirus DNA loads in human immunodeficiency virus–positive women with high-grade cervical lesions are strongly elevated. J Clin Microbiol. 2003;41:2763-2767. PubMedGoogle ScholarCrossref 8. Gilson RJ, Shupack JL, Friedman-Kien AE, et al. A randomized, controlled, safety study using imiquimod for the topical treatment of anogenital warts in HIV-infected patients. AIDS. 1999;13:2397-2404. PubMedGoogle ScholarCrossref

Journal

Archives of DermatologyAmerican Medical Association

Published: Feb 1, 2006

Keywords: genital warts,human papillomavirus,dna,suppository,surgical procedures, operative,anus,imiquimod,hiv infections,ablation

References