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Review ISSN 1975-7425(Print) / ISSN: 2288-016X(Online) http://dx.doi.org/10.14777/kjutii.2014.9.2.68 Korean J Urogenit Tract Infect Inflamm 2014;9(2):68-73 성기단순포진의권고치료 박흥재 성균관대학교의과대학강북삼성병원비뇨기과학교실 Recommended Managements for the Herpes Genitalia Heung Jae Park Department of Urology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea Herpes simplex virus (HSV) is a member of herpesviridae family viruses, which belong to DNA viruses. HSV-associated diseases are one of the most widespread infection and most genital herpes is caused by HSV type 2 (HSV-2). Treatment of genital herpes is complex. In addition to administration of the standard antiviral medications, an ideal management protocol should also address various aspects of the disease. Oral acyclovir, valacyclovir, and famciclovir are recommended for routine treatment. Long-term suppressive therapy is effective in reducing recurrence rate as well as the risk of transmission to others. However, antiviral drugs cannot cure HSV infection and persist during the lifetime of the host, often in latent form. Management of the sex partner, appropriate counseling, and prevention advice or education are equally important in management of genital herpes. This review provides a summary of several important recent guidelines regarding recommended management for the herpes genitalia. Keywords: Herpes genitalis; Antiviral agents; Therapy Copyright 2014, Korean Association of Urogenital Tract Infection and Inflammation. All rights reserved. This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Received: 19 February, 2014 Revised: 3 March, 2014 Accepted: 3 March, 2014 Correspondence to: Heung Jae Park Department of Urology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29, Saemunan-ro, Jongno-gu, Seoul 110-746, Korea Tel: +82-2-2001-2237, Fax: +82-2-2001-2247 E-mail: tigerhj@dreamwiz.com 서 론 단순포진은전세계정상성인의약 60-90% 에서감염이확인될정도로널리퍼져있는감염질환이다. 1 이중성기단순포진 (genital herpes) 은궤양성성매개감염 (ulcerative sexually transmitted infection) 중가장흔한원인이다. 1 주로 herpes simplex virus (HSV) 2형의감염이지만최근 1형에의한감염도증가하는추세이다. 2 한번감염이일어나면바이러스는평생인체내에잠복형태로존재하며, 면역이저하된환자에서는심각한합병증을일으키기도한다. 또한이러한병의잠복성으로재발이매우흔하고환자에게정신적인스트 레스를주게된다. 하지만, 아직까지바이러스를완전히치료할수있는치료법은없는상태이며감염을예방할수있는백신도개발되지않았다. 국내에서이루어진산부인과및비뇨기과외래를방문한환자들을대상으로한설문조사에서도재발성성기단순포진을경험한적이있는환자의비율이전체방문자중 39.5% 를차지하였다. 3 대표적인치료가이드라인인, British Association for Sexual Health and HIV, Centers for Disease Control and Prevention (CDC), European guideline for the management of genital herpes 등의치료법에대한지침들사이에약간씩차이가 68

Heung Jae Park. Recommended Managements for the Herpes Genitalia 69 Table 1. Recommended treatment of initial genital herpes in Korean guidelines 11 Grade of Regimen recommendation A a Recommended regimens for first clinical episode of genital herpes - Valacyclovir 1 g orally twice a day for 7-10 - 250 mg orally three times a day for 7-10 - 400 mg orally three times a day for 7-10 - 200 mg orally five times a day for 7-10 days A Intravenous (IV) acyclovir therapy should be provided for patients who have severe herpes simplex virus disease that necessitate hospitalization. The recommended regimen is acyclovir 5-10 mg/kg IV every 8 hours for 2-7 days or until clinical improvement is observed, followed by oral antiviral therapy to complete at least 10 days of total therapy. A It s more effective to initiatethe antiviral therapy as early as possible after onset of the clinical episode. - Valacyclovir within 3 days - within 5 days - within 5-7 days Valacyclovir, famciclovir, acyclovir are all effective in reducing the severity and duration of episode. Choice should be made by individual clinicians, taking cost of therapy and likely compliance into account. a :Evidence at level Ia (meta-analysis of randomized controlled trials) or Ib (at least one randomized controlled trial). Adapted from sexually transmitted infections Korean guidelines, with permission. 있어혼돈스러운부분도있다. 이런지침들중 2010년에개정된유럽및 CDC 가이드라인과이를토대로 2011년도에한국질병관리본부와대한요로생식기감염학회에서발간한성매개감염진료치침을정리하고자한다. 본 론 1. 최초발현감염 (First-Episode Genital Herpes) 최초발현성기단순포진에서항바이러스요법은증상을경감하고부작용을예방하는데매우효과적인치료로, 임상적진단만으로도항바이러스요법을시작할수있다. 증상시작 5일이내이거나새로운병변이계속생기는환자들에서항바이러스제제치료를시작하는데, 현재사용이가능한 3가지약물 (acyclovir, valacyclovir, famciclovir) 모두증상의정도및기간을감소시키는데효과적이다. 4-6 하지만항바이러스제는잠복해있는바이러스가완전히박멸되지않고, 치료를중단했을때재발을억제할수도없다. 7,8 또한바르는국소항바이러스요법 (topical agents) 은효과가경구용약물보다떨어지고이런국소항바이러스를사용하는것이 acyclovir-resistant strains와관련성을가지고있기때문에권장되지않는다. 9 약물의정맥주사는환자가약을삼킬수없거나구토등으로경구용약물의복용이불가능한경우에고려할수있다. 유럽가이드라인에서는 acyclovir 200 mg 1일 5회, acyclovir 400 mg 1일 3회, famciclovir 250 mg 1일 3회, valacyclovir 500 mg 1일 2회를권장하고있고기간은 5일로서술하고있다. 5 하지만많은수의환자들이 5일이상증상이지속되므로증상이지속되고새로운병변이생기거나합병증이있는경우에는 5일이상사용하도록권하고있다. 4 CDC 가이드라인은 7-10 일을사용할것을권고하고있고, valacyclovir의경우 1 g 1일 2회로용량에약간의차이가있고 10일이후에도상처회복이지연되는경우에는치료기간을연장하라고권유한다. 4,5,10 Table 1은성매개감염진료지침 (2011년) 의권장요법이다. 11 Table 1의여러요법들중 acyclovir 400 mg 하루 3회, 7-10일간경구투여방법은임상시험을한바없으며미국 Food and Drug Administration (FDA) 에서도승인되지않았으나 CDC에서는권유하는방법이다. 4 반면 acyclovir 200 mg 하루 5회또는 valacyclovir 1 g 하루 2회, 7-10 일간투여하는방법은 randomized controlled trials 로효과가증명되었고 FDA 승인및 CDC 권장요법이다. 4 국내보험기준은 acyclovir의경우단순포진치료로 200 mg을 1일 5회 (4시간간격 ), 5일까지허가되어있고, 단순포진예방에사용하는경우는 200 mg 1일 4회 (6시간간격 ), 또는 400 mg 1일 2회그후 200 mg 1일 2-3 회로감량하도록되어있다. 정맥주사의경우는 5 mg/kg를 8시간마다 intravenous (IV), 5일이허가사항이다 ( 소아 250 mg/m 2 ). Valacyclovir는치료의경우 1회 500 mg 1일 2회, 재발성 5일, 증상이심하면 10일까지투여할수있고, 재발억제를위해서는 1일 500 mg (1회또는 2회분복 ), 면역저하환자는 500 mg 1일 2회로되어있다. 안전한성생활을병행하는경우억제요법으로성기포진전염감소를위해서는연간 9회이하로재발하고면역기능이정상인이성애성인의경우 500 mg 1일 1회로되어있다. 는초발성성기단순포진은 250 mg 1일 3회, 5일간사용하게되어있고, 급성재발성성기단순포진은 125 mg 1일 2회, 5일간이허가사항이다. 재발성성기단순포진의억제는 250 mg 1일 2회로되어있다. 이외에보존적치료로 saline bathing, 국소진통요법을같이할수있다. 국소마취제를사용하는것은 sensitization 의문제가있을수있으나 lidocaine은이런민감반응이극히드물어성기단순포진에서도젤또는연고의형태로사용이가능하다. 하지만, benzocaine 은민감반응의문제로사용이금지되어있다. 12 2. 합병증의치료 (Treatment of Genital Herpes Complications) 요정체, 뇌수막염, 전신증상이심한경우나치료에부정적

70 Heung Jae Park. Recommended Managements for the Herpes Genitalia Table 2. Recommended treatment of recurrent genital herpes in European and Centers for Disease Control and Prevention (CDC) guidelines 4,5 European guidelines (2010) 5 days regimen Short-course regimen Valacylcovir Valacylcovir CDC guidelines (2010) Valacyclovir 200 mg, five times a day 400 mg, three times a day 125 mg, twice a day 800 mg, three times a day for 2 days 1 g, twice a day for 1 day for 3 days 400 mg, three times a day for 5 days 800 mg, twice a day for 5 days 800 mg, three times a day for 2 days 125 mg, twice a day for 5 days 1 g, twice a day for 1 day 500 mg once, followed by 250 mg twice a day for 2 days for 3 days 1 g, once a day for 5 days Modified from the European guideline for the management of genital herpes and sexually transmitted disease treatment guidelines of CDC. 인주위환경인경우입원을고려할수있고, 도뇨관유치가필요한경우에는치골상부방광루설치술이증상완화에더도움이될지고려해야한다. 5 Superinfection 은매우드물지만감염 2주째에발생할수있고국소증상이다시재발하는경우 (recrudescence) 에의심할수있으며 candida 감염이흔하게관련되어있다. 5 위와같이중증의상태를보이는경우 intravenous acyclovir 치료가필요하고, 용량은 5-10 mg/kg IV, 8시간간격, 2-7일정도또는임상적인호전을보일때까지투여하며이후에경구항바이러스제로바꾸고적어도전체치료기간은 10일정도가필요하다. 신장기능이저하된환자에서는 acyclovir 의용량조절이필요하다 (CDC 가이드라인, 2010). 4,6 3. 재발성성기단순포진 (Recurrent Genital Herpes) 재발성성기단순포진의치료는크게간헐적일시요법 (episodic antiviral treatment), 지속억제요법 (suppressive therapy), 보존적치료 (supportive therapy only) 로나누어볼수있다. 많은수의환자들에서증상이경미한경우에는생리식염수 (saline bathing), 국소바세린도포 (topical petroleum jelly) 등과같은보존적치료만으로도충분하다. 1) 간헐적일시요법 (episodic antiviral therapy for recurrent genital herpes), valacyclovir 그리고 famciclovir 3가지약물모두재발성성기단순포진의증상정도및기간을줄이는데효과적이다. 약물을투여하는경우증상기간을평균 1-2일정도단축할수있고, 약제들간의치료효과비교연구에서더 Table 3. Recommended treatment of recurrent genital herpes in Korean guidelines 11 Grade of Regimen recommendation A a Recommended regimens for recurrent genital herpes - Valacyclovir 500 mg orally twice a day for 5 - Valacyclovir 1 g orally once a day for 5-125 mg orally twice a day for 5-400 mg orally three times a day for 5-800 mg orally three times a day for 2 days B b It s more effective to initiate the antiviral therapy as early as possible after onset of the clinical episode. - Valacyclovir within 12 hours - within 6 hours Valacyclovir, famciclovir, acyclovir are all effective in reducing the severity and duration of episode. Choice should be made by individual clinicians, taking cost of therapy and likely compliance into account. a :Evidence at level Ia (meta-analysis of randomized controlled trials) or Ib (at least one randomized controlled trial). b :Evidence at level IIa (at least one well-designed controlled study without randomization), IIb (at least one other type of well-designed quasi-experimental study) or III (well-designed non-experimental descriptive studies). Adapted from sexually transmitted infections Korean guidelines, with permission. 우월한약물은없었다. 13-15 치료효과를나타내기위해서는병변이시작하여 1일이내이거나전구증상이있을때치료를시작해야한다. 16 Table 2는유럽및 CDC 가이드라인에서제시하고있는 3가지약물의투여방법및기간이고, 5,6 Table 3은성매개감염진료치침 (2011년) 의권고안이다. 11 2) 지속억제요법 성기단순포진환자중연간 6회이상재발하는환자의 70-80% 에서지속억제요법이효과가있는것으로보고되고있다. 17-20 이런억제요법은재발횟수가적은환자들에서도효과가있다. 5 를최대 6년간, valacylcovir 나 famciclovir 는최대 1년간사용한환자에서안정성과효과는잘확립되어있고, 자주재발하는환자들에서간헐적일시요법에비해서지속적인억제요법이삶의질향상에더효과가좋았다는보고도있다. 21,22 재발성성기단순포진의재발빈도는시일이지나면서점점줄어들기때문에억제요법을하는동안에정기적으로환자와지속요법을유지할지에대해서상의할필요가있다. 의적절한하루투약용량은 800 mg이다. 5 한연구에서 200 mg 1일 4회복용이 400 mg 1일 2회복용보다아주미미하게우월한것으로보고되었다. 23 Valacyclovir 250 mg 1일 2회복용법은 acyclovir 400 mg 1일 2회요법과거의동일한효과가있었다. 5 1일 1회요법은성기단순포진의재발을예방하지는못하였고, valacyclovir는 1일 1회

Heung Jae Park. Recommended Managements for the Herpes Genitalia 71 Table 4. Recommended suppressive treatment of recurrent genital herpes in Korean guidelines 11 Grade of Regimen recommendation Suppressive therapy for recurrent genital herpes - Valacyclovir 500 mg orally once a day ( 9 episodes per year), or - Valacyclovir 1,000 mg orally once a day ( 10 episodes per year), or - 250 mg orally twice a day, or - 400 mg orally twice a day A Safety and efficacy have been documented among patients receiving daily therapy with: - Valacyclovir for 1 year - for 4 months - for 6 years Suppressive therapy for recurrent genital herpes was not included in the health insurance allowance benefit in Korea. a :Evidence at level Ia (meta-analysis of randomized controlled trials) or Ib (at least one randomized controlled trial). Adapted from sexually transmitted infections Korean guidelines, with permission. A a Table 5. CDC recommended episodic and suppressive treatment of genital herpes in persons with HIV 6 Episodic infection (for 5-10 days) Daily suppressive therapy Valcyclovir Valcyclovir 400 mg, three times a day 1 g, twice a day 400-800 mg, twice to three times a day CDC: Centers for Disease Control and Prevention, HIV: human immunodeficiency virus. Adapted from the sexually transmitted disease treatment guidelines of CDC. abstinence) 과함께 valacylcovir 억제요법을고려할수있다. 5 4. Human Immunodeficiency Virus 감염환자에서의치료 요법과 1일 2회요법이같은효과를보이는지에대해서는이견이있다. 5 일년에 10회미만의재발을보이는환자의경우에는 valcyclovir 1일투여량이 500 mg이적당하지만, 10회이상재발하는경우에는 250 mg 1일 2회또는 1 g 1일 1회요법이필요할수있다고유럽가이드라인에서제시하고있고, 5,24 CDC 가이드라인에서는 valacyclovir 500 mg 1일 1회요법은다른 valacyclovir 또는 acyclovir 요법들과비교해서 1년에 10회이상재발하는환자에서는효과가떨어진다고서술하고있는차이점을보인다 (Table 4). 6 Valacyclovir 500 mg 1일 1회요법과 famciclovir 250 mg 1일 2회요법간의억제효과에차이는없었고, 임상적인반응이불충분한일부의환자에서는억제용량을 2배로증가할필요가있다. 25 일반적인용량에서혈액검사를통한모니터링은불필요하고, valacyclovir에서간혹경미한두통이나오심이나타날수있다. 5 Table 4는 CDC 가이드라인및성매개감염진료지침 (2011 년 ) 의억제요법들로두지침에차이는없다. 6,11 3) 지속요법중바이러스흘림및전파 (viral shedding and transmission on suppressive therapy) 무증상바이러스흘림 (subclinical virus shedding) 은 HSV-1, HSV-2 모두에서발생하나, HSV-2 에서보다흔하게발생하고감염후첫 1년에가장많이생기는것으로보고된다. 5 3가지약제모두증상및무증상바이러스흘림을억제한다. 5,6,11 바이러스흘림의억제가항상감염의전파를감소시키는것은아니지만, 1년에 10회미만의재발을보이는환자에서 valacyclovir 500 mg 1일 1회억제요법은 serodiscordant couples에서감염전파를약 50% 정도감소시키는것으로보고되었다. 26 그러므로이런경우에는콘돔의사용및선택적인금욕 (sexual 1) 최초발현감염 면역결핍환자에서 HSV 감염은지속적이고심한형태로나타날수있다. Human immunodeficiency virus (HIV) 감염환자에서발생한 HSV 병변은심하고, 통증을동반하며, 비정형적으로나타날수있으며, HSV 흘림현상도증가한다. 11 HIV 감염환자들에서최초발현성기단순포진에대한임상시험은없지만, 대부분의전문가들은일반적인용량보다증량된요법을권장한다. 5 하지만, 정상적인 cluster of differentiation 4 (CD4) 수치를보이는경우에는표준요법을고려할수있다. 5 HIV 가진행된경우에는평균용량의 2배를고려해야하며, 3-5일이후에도새로운병변이형성되는경우에는좀더고용량을사용해야한다. 5,6,11 유럽가이드라인에서제시하고있는용법은다음과같다. 5 (1) 200-400 mg 1일 5회 (2) 400-800 mg 1일 3회 (3) Valacyclovir 500 mg-1 g 1일 2회 (4) 250-500 mg 1일 3회치료기간은 5-10일, 적어도재상피화가이루어질때까지필요하다. 2) 재발성감염 CDC 가이드라인에서제시하고있는재발성감염에서의간헐적또는억제요법은 Table 5와같다. 6 항바이러스치료에도병변이지속되거나재발하는경우에는 HSV resistance 를고려해서 viral isolate 및 sensitivity test 가필요하다. 9 이런경우에는 HIV 전문가에게자문을구해야하며다른치료방법을모색해야한다. 에저항성을가지는경우에는 valacyclovir 및 famciclovir 에도대부분저항

72 Heung Jae Park. Recommended Managements for the Herpes Genitalia 성을보인다. 이런경우에는 foscarnet (40 mg/kg IV, 8시간간격 ) 또는 cidofovir (5 mg/kg, 1주 1회 ) 가효과가있을수있다. 6 매일억제요법을하는경우가간헐적요법에비해서 acyclovir-resistant HSV의발생이더적었다는보고가있다. 27 5. 백신이론적으로바이러스의전파를막는가장좋은방법은백신이지만, 성기단순포진에대한효과적인백신은아직개발되지않았다. 28 일부연구들에서 HSV type 2 glycoprotein D 백신이 HSV-seronegaive (HSV-1, 2 모두음성인경우 ) 여성의성기단순포진감염을예방하는효과가보고되었지만, 남성또는 HSV-1에양성인여성에서는예방효과가없었다. 29,30 결 론 성기단순포진은치료는가능하지만완치는불가능한질환이다. 치료는개인의상황을고려해야하며, 여러용법들중에서환자에게가장편한용법에대한상담도필요하다. 또한이런약물투여외에도질환성격이나, 병의전파를예방하기위한상담그리고에이즈와의관계등에대해서도교육이필요하다. REFERENCES 1. Fatahzadeh M, Schwartz RA. Human herpes simplex virus infections: epidemiology, pathogenesis, symptomatology, diagnosis, and management. J Am Acad Dermatol 2007;57: 737-63. 2. Xu F, Sternberg MR, Kottiri BJ, McQuillan GM, Lee FK, Nahmias AJ, et al. Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. JAMA 2006;296:964-73. 3. Lee CB, Choe HS, Hwang SJ, Lee SJ, Cho YH. Epidemiological characteristics of genital herpes and condyloma acuminata in patients presenting to urologic and gynecologic clinics in Korea. J Infect Chemother 2011;17:351-7. 4. Katz AR, Lee MV, Wasserman GM. Sexually transmitted disease (STD) update: a review of the CDC 2010 STD treatment guidelines and epidemiologic trends of common STDs in Hawai'i. Hawaii J Med Public Health 2012;71:68-73. 5. Patel R, Alderson S, Geretti A, Nilsen A, Foley E, Lautenschlager S, et al; IUSTI/WHO Europe. European guideline for the management of genital herpes, 2010. Int J STD AIDS 2011;22: 1-10. 6. Workowski KA, Berman SM; Centers for Disease Control and Prevention. Sexually transmitted disease treatment guidelines, 2010. MMWR Recomm Rep 2010;59:20-5. 7. Corey L, Benedetti J, Critchlow C, Mertz G, Douglas J, Fife K, et al. Treatment of primary first-episode genital herpes simplex virus infections with acyclovir: results of topical, intravenous and oral therapy. J Antimicrob Chemother 1983;12(Suppl B):79-88. 8. Fife KH, Barbarash RA, Rudolph T, Degregorio B, Roth R. Valaciclovir versus acyclovir in the treatment of first-episode genital herpes infection. Results of an international, multicenter, double-blind, randomized clinical trial. The Valaciclovir International Herpes Simplex Virus Study Group. Sex Transm Dis 1997;24:481-6. 9. Reyes M, Shaik NS, Graber JM, Nisenbaum R, Wetherall NT, Fukuda K, et al; Task Force on Herpes Simplex Virus Resistance. -resistant genital herpes among persons attending sexually transmitted disease and human immunodeficiency virus clinics. Arch Intern Med 2003;163:76-80. 10. Martin JM, Villalon G, Jorda E. Update on the treatment of genital herpes. Actas Dermosifiliogr 2009;100:22-32. 11. Korea Centers for Disease Control and Prevention, Korean Association of Urogenital Tract Infection and Inflammation. Sexually transmitted infections Korean guidelines. Seoul: Korea Centers for Disease Control and Prevention, Korean Association of Urogenital Tract Infection and Inflammation, 2011. 12. Weightman W, Turner T. Allergic contact dermatitis from lignocaine: report of 29 cases and review of the literature. Contact Dermatitis 1998;39:265-6. 13. Nilsen AE, Aasen T, Halsos AM, Kinge BR, Tjotta EA, Wikstrom K, et al. Efficacy of oral acyclovir in the treatment of initial and recurrent genital herpes. Lancet 1982;2:571-3. 14. Sacks SL, Aoki FY, Diaz-Mitoma F, Sellors J, Shafran SD. Patient-initiated, twice-daily oral famciclovir for early recurrent genital herpes. A randomized, double-blind multicenter trial. Canadian Study Group. JAMA 1996;276:44-9. 15. Spruance SL, Tyring SK, DeGregorio B, Miller C, Beutner K. A large-scale, placebo-controlled, dose-ranging trial of peroral valaciclovir for episodic treatment of recurrent herpes genitalis. Valaciclovir HSV Study Group. Arch Intern Med 1996;156: 1729-35. 16. Spruance SL, Overall JC Jr, Kern ER, Krueger GG, Pliam V, Miller W. The natural history of recurrent herpes simplex labialis: implications for antiviral therapy. N Engl J Med 1977;297: 69-75. 17. Mertz GJ, Loveless MO, Levin MJ, Kraus SJ, Fowler SL, Goade D, et al. Oral famciclovir for suppression of recurrent genital herpes simplex virus infection in women. A multicenter, double-blind, placebo-controlled trial. Collaborative Genital Herpes Research Group. Arch Intern Med 1997; 157:343-9. 18. Diaz-Mitoma F, Sibbald RG, Shafran SD, Boon R, Saltzman RL. Oral famciclovir for the suppression of recurrent genital herpes: a randomized controlled trial. Collaborative Genital Herpes Research Group. JAMA 1998;280:887-92. 19. Reitano M, Tyring S, Lang W, Thoming C, Worm AM, Borelli S, et al. Valaciclovir for the suppression of recurrent genital

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