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Спонтанный клиренс вируса папилломы человека в результате супрессивной терапии ациклическими нуклеозидами рецидивирующей герпес-вирусной инфекции, локализованной в области гениталий
Спонтанный клиренс вируса папилломы человека в результате супрессивной терапии ациклическими нуклеозидами рецидивирующей герпес-вирусной инфекции, локализованной в области гениталий
Тапильская Н.И., Воробцова И.Н., Глушаков Р.И. Спонтанный клиренс вируса папилломы человека в результате супрессивной терапии ациклическими нуклеозидами рецидивирующей герпес-вирусной инфекции, локализованной в области гениталий. Гинекология. 2017; 19 (3): 55–61.
DOI: 10.26442/2079-5696_19.3.55-61
DOI: 10.26442/2079-5696_19.3.55-61
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Аннотация
На сегодняшний день не существует методов лечения папилломавирусной инфекции (ПВИ). По накопленным научным данным известно, что у 80% инфицированных вирусом папилломы человека (ВПЧ) пациенток наблюдается спонтанный клиренс инфекции, что связано в том числе и с детерминированным иммунным ответом. По данным эпидемиологических исследований, герпес-вирусная инфекция, локализованная в области гениталий, является фактором риска персистенции ПВИ. Нами с 2015 по 2017 г. проведено параллельное исследование по изучению влияния противогерпетической терапии ациклическими нуклеозидами в супрессивном режиме у пациенток (n=32) в возрасте от 28 до 34 лет (средний возраст – 30,4±2,1 года) с рецидивирующей герпетической инфекцией, локализованной в области гениталий, на течение сопутствующей ПВИ. Всем пациенткам назначался валацикловир в профилактическом режиме по 500 мг/сут в течение не менее 6 мес. После терапии герпес-вирусной инфекции констатирована элиминация не менее 1 типа ВПЧ у 14 (43,75%) пациенток, элиминация 16-го типа вируса была достигнута только в 15,4% случаев, 18-го – в 25%. Снижение вирусной нагрузки ВПЧ произошло у 20 (62,5%) пациенток, полная элиминация вируса зафиксирована у 15,6%. Значимая и высокая вирусная нагрузка ВПЧ сохранялась у 31,3 и 37,5% пациенток соответственно.
Ключевые слова: валацикловир, Валвир, герпес, вирус папилломы человека, toll-подобные рецепторы.
Objectives. This study demonstrated a spontaneous clearance of the HPV follow the suppressive therapy of a recurrent HSV infection with acyclic nucleosides. Study design. We carried out a parallel observational study from 2015 to 2017. Herpes suppressive therapy with acyclic nucleosides (valacyclovir of 500 mg per day) during a 6 months is used to treat patients (n=32) aged 28 to 34 years (mean age 30.4±2.1 years) who have recurrent genital HSV infection and HPV infection both. The detection of HPV by RT-PCR before and after ant-herpetic therapy was investigated.
Results. After treatment of HSV infection eradication of the one types of HPV was achieved in 43.75% cases, eradication of HPV-16 was achieved only in 15.4% (in 2 out of 13 patients) of cases, eradication HPV-18 was achieved in 25% (in 4 out of 16 patients) of cases. Decreasing of viral load occurred in 62.5% patients, full HPV-clearance was recorded in 15.6% of patients, but the high viral-load of HPV infection was preserved in 37.5% of the cases.
Key words: valacyclovir, Valvir, herpes, human papilloma virus, TLR.
Ключевые слова: валацикловир, Валвир, герпес, вирус папилломы человека, toll-подобные рецепторы.
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Objectives. This study demonstrated a spontaneous clearance of the HPV follow the suppressive therapy of a recurrent HSV infection with acyclic nucleosides. Study design. We carried out a parallel observational study from 2015 to 2017. Herpes suppressive therapy with acyclic nucleosides (valacyclovir of 500 mg per day) during a 6 months is used to treat patients (n=32) aged 28 to 34 years (mean age 30.4±2.1 years) who have recurrent genital HSV infection and HPV infection both. The detection of HPV by RT-PCR before and after ant-herpetic therapy was investigated.
Results. After treatment of HSV infection eradication of the one types of HPV was achieved in 43.75% cases, eradication of HPV-16 was achieved only in 15.4% (in 2 out of 13 patients) of cases, eradication HPV-18 was achieved in 25% (in 4 out of 16 patients) of cases. Decreasing of viral load occurred in 62.5% patients, full HPV-clearance was recorded in 15.6% of patients, but the high viral-load of HPV infection was preserved in 37.5% of the cases.
Key words: valacyclovir, Valvir, herpes, human papilloma virus, TLR.
Полный текст
Список литературы
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19. Mesquita PMM, Preston-Hurlburt P, Keller MJ et al. Role of Interleukin 32 in Human Immunodeficiency Virus Reactivation and Its Link to Human Immunodeficiency Virus-Herpes Simplex Virus Coinfection. J Infect Dis 2017; 215 (4): 614–22. DOI: https://doi.org/10.1093/infdis/jiw612
20. Huang HS, Lambert PF. Use of an in vivo animal model for assessing the role of integrin a6b4 and syndecan-1 in early steps in papillomavirus infection. Virology. 2012; 433: 395–400.
21. Cermelli C, Orsi CF, Ardizzoni A et al. Herpes simplex virus type 1 dysregulates antifungal defenses preventing monocyte activation and downregulating toll-like receptor-2. Microbiol Immunol 2008; 52 (12): 575–84.
22. Shannon B, Gajer P, Yi TJ et al. Distinct effects of the cervicovaginal microbiota and herpes simplex type 2 infection on female genital tract immunology. J Infect Dis 2017; 215 (9): 1366-75. DOI: https://doi.org/10.1093/infdis/jix088
23. Plotkin BJ, Sigar IM, Tiwari V, Halkyard S. Herpes simplex virus (HSV) modulation of Staphylococcus aureus and Candida albicans initiation of HeLa 299 cell-associated biofilm. Curr Microbiol 2016; 72: 529–37. DOI 10.1007/s00284-015-0975-7
24. Satapathy S, Batra J, Jeet V et al. MicroRNAs in HPV associated cancers: small players with big consequences. Expert Rev Mol Diagn 2017; 17 (7): 711–22. DOI: 10.1080/14737159.2017.1339603
25. Косарев В.В., Бабанов С.А. Клиническая фармакология и рациональная фармакотерапия. М.: Вузовский учебник; ИНФРА-М, 2012. / Kosarev V.V., Babanov S.A. Klinicheskaia farmakologiia i ratsional'naia farmakoterapiia. M.: Vuzovskii uchebnik; INFRA-M, 2012. [in Russian]
2. Tapilskaya N.I., Vorobtsova I.N., Gaidukov S.N., Proshin S.N. Efficacy and safety of imiquimod in the treatment of subclinical and clinical forms of persistent cervical papillomavirus infection in patients of early reproductive age. Gynecology. 2015; 17 (1): 14–7. [in Russian]
3. Rawls W, Tompkins W, Figueroa M, Melnick J. Herpesvirus type 2: association with carcinoma of the cervix. Science (New York, NY) 1968; 161 (847): 1255.
4. Hausen H. Human genital cancer: synergism between two virus infections or synergism between a virus infection and initiating events? Lancet 1982; 320 (8312): 1370–2.
5. Vonka V, Kanka J, Hirsch I et al. Prospective study on the relationship between cervical neoplasia and herpes simplex type-2 virus. II. Herpes simplex type-2 antibody presence in sera taken at enrollment. Int J Cancer 1984; 33 (1): 61–6.
6. Lehtinen M, Koskela P, Jellum E et al. Herpes simplex virus and risk of cervical cancer: a longitudinal, nested case-control study in the Nordic countries. Am J Epidemiol 2002: 156 (8): 687–92.
7. Cao S, Gan Y, Dong X, Lu Z. Herpes simplex virus type 2 and the risk of cervical cancer: a meta-analysis of observational studies. Arch Gynecol Obstet 2014; 290: 1059–66. DOI 10.1007/s00404-014-3365-7
8. Smith JS, Herrero R, Bosetti C et al. Herpes simplex virus-2 as a human papillomavirus cofactor in the etiology of invasive cervical cancer. J Natl Cancer Inst 2002; 94: 1604–13.
9. Hoffmann M, Quabius ES, Tribius S et al. Human papillomavirus infection in head and neck cancer: the role of the secretory leukocyte protease inhibitor. Oncol Rep 2013; 29: 1962–8.
10. Genital'nyi gerpes. Pod red. A.A.Kubanovoi. Klinicheskie rekomendatsii. Rossiiskoe obshchestvo dermatovenerologov. M.: DEKS-Press, 2010. [in Russian]
11. Hibma MH. The immune response to papillomavirus during infection persistence and regression. Open Virol J 2012; 6: 241–8. DOI: 10.2174/1874357901206010241
12. Amador-Molina A, Hernández-Valencia JF, Lamoyi E et al. Role of innate immunity against human papillomavirus (HPV) infections and effect of adjuvants in promoting specific immune response. Viruses 2013; 5 (11): 2624–42. DOI: 10.3390/v5112624
13. Proshin S.N., Glushakov R.I., Shabanov P.D. i dr. Znachenie ekspressii TLR-retseptorov dlia vybora farmakologicheskoi korrektsii patologii sheiki matki i endometriia. Geny i kletki. 2011; 6 (1): 91–7. [in Russian]
14. Wahid B, Ali A, Idrees M, Rafique S. Immunotherapeutic strategies for sexually transmitted viral infections: HIV, HSV and HPV. Cell Immunol 2016; 310: 1–13. DOI: 10.1016/j.cellimm.2016.08.001
15. Jemon K, Leong CM, Ly K et al. Suppression of the CD8+ T cell response by human papillomavirus type 16 E7 occurs in Langerhans cell-depleted mice. Sci Rep 2016; 6: 34789. DOI: 10.1038/srep34789
16. Guidry JT, Scott RS. The interaction between human papillomavirus and other viruses. Virus Res 2017; 231: 139–47. DOI: 10.1016/j.virusres.2016.11.002
17. Joseph G Skeate, Tania B et al. Herpes simplex virus downregulation of secretory leukocyte protease inhibitor enhances human papillomavirus type 16 infection. J Gen Virol 2016; 97: 422–34. DOI: 10.1099/jgv.0.000341
18. Woodham AW, Raff AB, Raff LM et al. Inhibition of Langerhans cell maturation by human papillomavirus type 16: a novel role for the annexin A2 heterotetramer in immune suppression. J Immunol 2014: 192: 4748–57.
19. Mesquita PMM, Preston-Hurlburt P, Keller MJ et al. Role of Interleukin 32 in Human Immunodeficiency Virus Reactivation and Its Link to Human Immunodeficiency Virus-Herpes Simplex Virus Coinfection. J Infect Dis 2017; 215 (4): 614–22. DOI: https://doi.org/10.1093/infdis/jiw612
20. Huang HS, Lambert PF. Use of an in vivo animal model for assessing the role of integrin a6b4 and syndecan-1 in early steps in papillomavirus infection. Virology. 2012; 433: 395–400.
21. Cermelli C, Orsi CF, Ardizzoni A et al. Herpes simplex virus type 1 dysregulates antifungal defenses preventing monocyte activation and downregulating toll-like receptor-2. Microbiol Immunol 2008; 52 (12): 575–84.
22. Shannon B, Gajer P, Yi TJ et al. Distinct effects of the cervicovaginal microbiota and herpes simplex type 2 infection on female genital tract immunology. J Infect Dis 2017; 215 (9): 1366-75. DOI: https://doi.org/10.1093/infdis/jix088
23. Plotkin BJ, Sigar IM, Tiwari V, Halkyard S. Herpes simplex virus (HSV) modulation of Staphylococcus aureus and Candida albicans initiation of HeLa 299 cell-associated biofilm. Curr Microbiol 2016; 72: 529–37. DOI 10.1007/s00284-015-0975-7
24. Satapathy S, Batra J, Jeet V et al. MicroRNAs in HPV associated cancers: small players with big consequences. Expert Rev Mol Diagn 2017; 17 (7): 711–22. DOI: 10.1080/14737159.2017.1339603
25. Kosarev V.V., Babanov S.A. Klinicheskaia farmakologiia i ratsional'naia farmakoterapiia. M.: Vuzovskii uchebnik; INFRA-M, 2012. [in Russian]
2. Тапильская Н.И., Воробцова И.Н., Гайдуков С.Н., Прошин С.Н. Оценка эффективности и безопасности применения имихимода в лечении субклинических и клинических проявлений персистирующей папилломавирусной инфекции шейки матки у пациенток раннего репродуктивного возраста. Гинекология. 2015; 17 (1): 14–7. / Tapilskaya N.I., Vorobtsova I.N., Gaidukov S.N., Proshin S.N. Efficacy and safety of imiquimod in the treatment of subclinical and clinical forms of persistent cervical papillomavirus infection in patients of early reproductive age. Gynecology. 2015; 17 (1): 14–7. [in Russian]
3. Rawls W, Tompkins W, Figueroa M, Melnick J. Herpesvirus type 2: association with carcinoma of the cervix. Science (New York, NY) 1968; 161 (847): 1255.
4. Hausen H. Human genital cancer: synergism between two virus infections or synergism between a virus infection and initiating events? Lancet 1982; 320 (8312): 1370–2.
5. Vonka V, Kanka J, Hirsch I et al. Prospective study on the relationship between cervical neoplasia and herpes simplex type-2 virus. II. Herpes simplex type-2 antibody presence in sera taken at enrollment. Int J Cancer 1984; 33 (1): 61–6.
6. Lehtinen M, Koskela P, Jellum E et al. Herpes simplex virus and risk of cervical cancer: a longitudinal, nested case-control study in the Nordic countries. Am J Epidemiol 2002: 156 (8): 687–92.
7. Cao S, Gan Y, Dong X, Lu Z. Herpes simplex virus type 2 and the risk of cervical cancer: a meta-analysis of observational studies. Arch Gynecol Obstet 2014; 290: 1059–66. DOI 10.1007/s00404-014-3365-7
8. Smith JS, Herrero R, Bosetti C et al. Herpes simplex virus-2 as a human papillomavirus cofactor in the etiology of invasive cervical cancer. J Natl Cancer Inst 2002; 94: 1604–13.
9. Hoffmann M, Quabius ES, Tribius S et al. Human papillomavirus infection in head and neck cancer: the role of the secretory leukocyte protease inhibitor. Oncol Rep 2013; 29: 1962–8.
10. Генитальный герпес. Под ред. А.А.Кубановой. Клинические рекомендации. Российское общество дерматовенерологов. М.: ДЭКС-Пресс, 2010. / Genital'nyi gerpes. Pod red. A.A.Kubanovoi. Klinicheskie rekomendatsii. Rossiiskoe obshchestvo dermatovenerologov. M.: DEKS-Press, 2010. [in Russian]
11. Hibma MH. The immune response to papillomavirus during infection persistence and regression. Open Virol J 2012; 6: 241–8. DOI: 10.2174/1874357901206010241
12. Amador-Molina A, Hernández-Valencia JF, Lamoyi E et al. Role of innate immunity against human papillomavirus (HPV) infections and effect of adjuvants in promoting specific immune response. Viruses 2013; 5 (11): 2624–42. DOI: 10.3390/v5112624
13. Прошин С.Н., Глушаков Р.И., Шабанов П.Д. и др. Значение экспрессии TLR-рецепторов для выбора фармакологической коррекции патологии шейки матки и эндометрия. Гены и клетки. 2011; 6 (1): 91–7. / Proshin S.N., Glushakov R.I., Shabanov P.D. i dr. Znachenie ekspressii TLR-retseptorov dlia vybora farmakologicheskoi korrektsii patologii sheiki matki i endometriia. Geny i kletki. 2011; 6 (1): 91–7. [in Russian]
14. Wahid B, Ali A, Idrees M, Rafique S. Immunotherapeutic strategies for sexually transmitted viral infections: HIV, HSV and HPV. Cell Immunol 2016; 310: 1–13. DOI: 10.1016/j.cellimm.2016.08.001
15. Jemon K, Leong CM, Ly K et al. Suppression of the CD8+ T cell response by human papillomavirus type 16 E7 occurs in Langerhans cell-depleted mice. Sci Rep 2016; 6: 34789. DOI: 10.1038/srep34789
16. Guidry JT, Scott RS. The interaction between human papillomavirus and other viruses. Virus Res 2017; 231: 139–47. DOI: 10.1016/j.virusres.2016.11.002
17. Joseph G Skeate, Tania B et al. Herpes simplex virus downregulation of secretory leukocyte protease inhibitor enhances human papillomavirus type 16 infection. J Gen Virol 2016; 97: 422–34. DOI: 10.1099/jgv.0.000341
18. Woodham AW, Raff AB, Raff LM et al. Inhibition of Langerhans cell maturation by human papillomavirus type 16: a novel role for the annexin A2 heterotetramer in immune suppression. J Immunol 2014: 192: 4748–57.
19. Mesquita PMM, Preston-Hurlburt P, Keller MJ et al. Role of Interleukin 32 in Human Immunodeficiency Virus Reactivation and Its Link to Human Immunodeficiency Virus-Herpes Simplex Virus Coinfection. J Infect Dis 2017; 215 (4): 614–22. DOI: https://doi.org/10.1093/infdis/jiw612
20. Huang HS, Lambert PF. Use of an in vivo animal model for assessing the role of integrin a6b4 and syndecan-1 in early steps in papillomavirus infection. Virology. 2012; 433: 395–400.
21. Cermelli C, Orsi CF, Ardizzoni A et al. Herpes simplex virus type 1 dysregulates antifungal defenses preventing monocyte activation and downregulating toll-like receptor-2. Microbiol Immunol 2008; 52 (12): 575–84.
22. Shannon B, Gajer P, Yi TJ et al. Distinct effects of the cervicovaginal microbiota and herpes simplex type 2 infection on female genital tract immunology. J Infect Dis 2017; 215 (9): 1366-75. DOI: https://doi.org/10.1093/infdis/jix088
23. Plotkin BJ, Sigar IM, Tiwari V, Halkyard S. Herpes simplex virus (HSV) modulation of Staphylococcus aureus and Candida albicans initiation of HeLa 299 cell-associated biofilm. Curr Microbiol 2016; 72: 529–37. DOI 10.1007/s00284-015-0975-7
24. Satapathy S, Batra J, Jeet V et al. MicroRNAs in HPV associated cancers: small players with big consequences. Expert Rev Mol Diagn 2017; 17 (7): 711–22. DOI: 10.1080/14737159.2017.1339603
25. Косарев В.В., Бабанов С.А. Клиническая фармакология и рациональная фармакотерапия. М.: Вузовский учебник; ИНФРА-М, 2012. / Kosarev V.V., Babanov S.A. Klinicheskaia farmakologiia i ratsional'naia farmakoterapiia. M.: Vuzovskii uchebnik; INFRA-M, 2012. [in Russian]
________________________________________________
2. Tapilskaya N.I., Vorobtsova I.N., Gaidukov S.N., Proshin S.N. Efficacy and safety of imiquimod in the treatment of subclinical and clinical forms of persistent cervical papillomavirus infection in patients of early reproductive age. Gynecology. 2015; 17 (1): 14–7. [in Russian]
3. Rawls W, Tompkins W, Figueroa M, Melnick J. Herpesvirus type 2: association with carcinoma of the cervix. Science (New York, NY) 1968; 161 (847): 1255.
4. Hausen H. Human genital cancer: synergism between two virus infections or synergism between a virus infection and initiating events? Lancet 1982; 320 (8312): 1370–2.
5. Vonka V, Kanka J, Hirsch I et al. Prospective study on the relationship between cervical neoplasia and herpes simplex type-2 virus. II. Herpes simplex type-2 antibody presence in sera taken at enrollment. Int J Cancer 1984; 33 (1): 61–6.
6. Lehtinen M, Koskela P, Jellum E et al. Herpes simplex virus and risk of cervical cancer: a longitudinal, nested case-control study in the Nordic countries. Am J Epidemiol 2002: 156 (8): 687–92.
7. Cao S, Gan Y, Dong X, Lu Z. Herpes simplex virus type 2 and the risk of cervical cancer: a meta-analysis of observational studies. Arch Gynecol Obstet 2014; 290: 1059–66. DOI 10.1007/s00404-014-3365-7
8. Smith JS, Herrero R, Bosetti C et al. Herpes simplex virus-2 as a human papillomavirus cofactor in the etiology of invasive cervical cancer. J Natl Cancer Inst 2002; 94: 1604–13.
9. Hoffmann M, Quabius ES, Tribius S et al. Human papillomavirus infection in head and neck cancer: the role of the secretory leukocyte protease inhibitor. Oncol Rep 2013; 29: 1962–8.
10. Genital'nyi gerpes. Pod red. A.A.Kubanovoi. Klinicheskie rekomendatsii. Rossiiskoe obshchestvo dermatovenerologov. M.: DEKS-Press, 2010. [in Russian]
11. Hibma MH. The immune response to papillomavirus during infection persistence and regression. Open Virol J 2012; 6: 241–8. DOI: 10.2174/1874357901206010241
12. Amador-Molina A, Hernández-Valencia JF, Lamoyi E et al. Role of innate immunity against human papillomavirus (HPV) infections and effect of adjuvants in promoting specific immune response. Viruses 2013; 5 (11): 2624–42. DOI: 10.3390/v5112624
13. Proshin S.N., Glushakov R.I., Shabanov P.D. i dr. Znachenie ekspressii TLR-retseptorov dlia vybora farmakologicheskoi korrektsii patologii sheiki matki i endometriia. Geny i kletki. 2011; 6 (1): 91–7. [in Russian]
14. Wahid B, Ali A, Idrees M, Rafique S. Immunotherapeutic strategies for sexually transmitted viral infections: HIV, HSV and HPV. Cell Immunol 2016; 310: 1–13. DOI: 10.1016/j.cellimm.2016.08.001
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Авторы
Н.И.Тапильская*1, И.Н.Воробцова1, Р.И.Глушаков2
1. ФГБОУ ВО «Санкт-Петербургский государственный педиатрический медицинский университет» Минздрава России. 194100, Россия, Санкт-Петербург, ул. Литовская, д. 2;
2. ФГБВОУ ВО «Военно-медицинская академия им. С.М.Кирова» Минобороны России. 194044, Россия, Санкт-Петербург, ул. Академика Лебедева, д. 6
*tapnatalia@yandex.ru
1. Saint Petersburg Pediatric University of the Ministry of Health of the Russian Federation. 194100, Russian Federation, Saint Petersburg, ul. Litovskaia, d. 2;
2. S.M.Kirov Medical Military Academy of the Ministry of Defence of the Russian Federation. 194044, Russian Federation, Saint Petersburg, ul. Akademika Lebedeva, d. 6
*tapnatalia@yandex.ru
1. ФГБОУ ВО «Санкт-Петербургский государственный педиатрический медицинский университет» Минздрава России. 194100, Россия, Санкт-Петербург, ул. Литовская, д. 2;
2. ФГБВОУ ВО «Военно-медицинская академия им. С.М.Кирова» Минобороны России. 194044, Россия, Санкт-Петербург, ул. Академика Лебедева, д. 6
*tapnatalia@yandex.ru
________________________________________________
1. Saint Petersburg Pediatric University of the Ministry of Health of the Russian Federation. 194100, Russian Federation, Saint Petersburg, ul. Litovskaia, d. 2;
2. S.M.Kirov Medical Military Academy of the Ministry of Defence of the Russian Federation. 194044, Russian Federation, Saint Petersburg, ul. Akademika Lebedeva, d. 6
*tapnatalia@yandex.ru
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