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The Korean Journal of Helicobacter and Upper Gastrointestinal Research Vol. 11, No. 2, 103-111, September 2011 Helicobacter pylori 의순차적제균요법 Sequential Therapy of Helicobacter pylori Infection Jong In Kim, Byung-Wook Kim Division of Gastroenterology, Department of Internal Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Incheon, Korea The standard therapy for Helicobacter pylori infection in Korea consists of a triple-drug regimen containing a proton pump inhibitor with two antibiotics such as clarithromycin, amoxicillin, and metronidazole. However, the eradication rate of this regimen is declining and a new regimen should be prompted. Among them, sequential therapy seems to be more effective than the conventional triple therapy. Sequential therapy, however, has only been tried in the limited countries such as Italy. To recommend this therapy in clinical practice, well-designed clinical trials should be performed in Korea since many host factors and bacterial factors influence the treatment outcomes. In this article, we are going to review the basic concepts and the results of previous clinical trials on sequential therapy. (Korean J Helicobacter Upper Gastrointest Res 2011;11:103-111) Key Words: Helicobacter pylori; Therapy 가톨릭대학교의과대학인천성모병원내과학교실소화기내과김종인, 김병욱접수일 :2011년 7월 20일승인일 :2011년 8월 23일연락처 : 김병욱인천시부평구부평동 665번지우편번호 : 403-720 가톨릭대학교인천성모병원소화기내과 Tel: 032-510-5052 Fax: 032-510-5987 E-mail: gastro@catholic.ac.kr 서론대한상부위장관ㆍ헬리코박터학회와대한소화기학회는 2009년 Helicobacter pylori (H. pylori) 치료법의조건으로 per protocol (PP) 분석에서 90% 이상, intention to treat (ITT) 분석에서 80% 이상의치료성공률을보이고심각한부작용발생률이 5% 이하여야한다고제시하였다. 1 그러나 H. pylori 제균치료성공률에대한국내메타분석에서도대부분이러한조건을만족하지못하고있으며, 2 국내를포함한 H. pylori 표준제균요법은점차그제균율이낮아지는경향을보이고있어 3 이에대한대책마련이필요하다. Zullo 등 4 은 omeprazole과 amoxicillin을 5일간투여한후, omeprazole과 clarithromycin, tinidazole을 5일간추가로투여하는순차적제균요법 (sequential therapy) 을처음소개하였고, 그제균율이 ITT분석에서 98% 에이른다고보고하였다. 이후에도순차적제균요법의제균율이대부분높게보고 되었으나일부에서는그반대의견도있어, 5 이에대한체계적인분석과논의가필요하다. 본논고에서는순차적제균요법이표준 3제요법의낮은제균율을대체할수있는대안으로받아들여질수있는지알아보고, 국내에서도입하기위한전제조건을알아보고자한다. 본론 1. 순차적제균요법의기본원리순차적제균요법은 2000년 Zullo 등 4 이처음소개하였는데, 이들의이전연구에서양성자펌프억제제와 amoxicillin 의 2제요법으로 14일간투약후제균에실패한환자에서 7일간 3제요법으로치료를하면제균율이훨씬높게나타나는것을확인하고 6 amoxicillin을포함한 2제요법은 7일이내투여하더라도제균율이약 50% 에이르고, 7 3제요법은위점막에서세균의밀도가낮을수록제균율이높다는것을 103

104 The Korean Journal of Helicobacter and Upper Gastrointestinal Research: 제 11 권제 2 호 2011 Table 1. Eradications Rates of 10 Days Sequential Therapy Study, year (Reference) Zullo 2000 (4) De Francesco 2001 (12) Zullo 2003 (13) Hassan 2003 (14) De Francesco 2004 (15) De Francesco 2004 (16) Zullo 2005 (17) Scaccianoce 2006 (18) Country of origin Patients enrolled Centers involved Study design First 5 days Italy 52 1 Single branch Italy 63 2 Double branch Italy 522 8 RCT Italy 152 3 Double branch Italy 45 2 RCT Italy 116 2 RCT Italy 89 3 RCT Italy 72 2 RCT Eso 20 mg bid Francavilla Italy 38 1 RCT Ome 1 mg/kg/day 2005 (19) a Amo 50 mg/kg/day Vaira 2007 (11) Sánchez-Delgado 2008 (28) Choi 2008 (31) Wu 2010 (10) Sirimontaporn 2010 (36) Molina-Infante 2010 (29) Pontone 2010 (20) Italy & USA 146 2 RCT Pan 20 mg bid Spain 139 6 Single branch PPI standard dose bid Korea 158 1 RCT Taiwan 115 3 Single branch Eso 40 mg bid Thailand 115 1 Single branch Lan 30 mg bid Spain 115 1 RCT Italy 84 1 Single branch Lan 30 mg bid Regimen Second 5 days Eso 20 mg bid Ome 1 mg/kg/day Cla 15 mg/kg/day Tin 20 mg/kg/day Pan 20 mg bid PPI standard dose bid Eso 40 mg bid Lan 30 mg bid Cla 1,000 mg qd Lan 30 mg bid Cla 1,000 mg qd ITT eradication rate (%) 98.0 93.8 92.0 93.4 95.6 94.8 94.4 94.4 94.7 91.1 84.2 77.9 92.3 95.0 76.5 83.3

김종인, 김병욱 :Helicobacter pylori 의순차적제균요법 105 Table 1. Continued Study, year (Reference) Paoluzi 2010 (21) Kwon 2010 (32) Zegarra Chang 2011 (38) Gao 2010 (33) Romano 2010 (22) Romano 2010 (22) Romano 2010 (22) Country of origin Patients enrolled Centers involved Study design First 5 days Italy 90 1 RCT Eso 20 mg bid Korea 98 1 Single branch Rab 20 md bid Peru 31 1 Single branch China 71 1 RCT Italy 125 6 RCT Italy 125 6 RCT Italy 125 6 RCT Albrecht Poland 54 1 RCT Ome 1 mg/kg 2011 (30) a Amo 50 mg/kg Tursi 2011 (23) Schmiloviz-Weiss 2011 (39) Italy 437 Various Single branch PPI standard dose bid Israel 124 3 Single branch Regimen Second 5 days Eso 20 mg bid Lev 250 mg bid Lev 500 mg bid Ome 1 mg/kg Cla 20 mg/kg Tin 20 mg/kg PPI standard dose bid ITT eradication rate (%) bid, twice a day; RCT, randomized controlled trial; Ome, omeprazole; Amo, amoxicillin; Cla, clarithromycin; Tin, tinidazole; Rab, rabeprazole; Eso, esomeprazole; Pan, pantoprazole; PPI, proton pump inhibitor; Met, metronidazole; Lan, lansoprazole; Lev, levofloxacin. a Studies performed in children. 86.0 91.8 73.0 80.6 80.8 96.0 96.8 83.3 91.1 92.7 고려하여, 8,9 치료기간을최소화하기위해 2제요법으로 5 일간투여한후 3제요법으로 5일간투약하는방법을고안하였다. 순차적제균요법의제균율이높은다른이유는첫 5일간 amoxicillin을투여하면 H. pylori 균주의세포벽이손상되어 clarithromycin과같은항생제가균주안으로침투하기쉬워지고, 세포벽이손상된 H. pylori 균주는 clarithromycin을밖으로내보내는채널이형성되지않아 clarithromycin에대한내성이발생하더라도항생제의효과가그대로유지되어제균효과를높인다는것이다. 또다른가능성이있는설명은표준 3제요법은항생제를 2가지사용하지만순차적제균요법은 3가지항생제를사 용하므로단순히추가된항생제의효과에의한것이라는설명이다. 한연구에서 10일간순차적제균요법을시행한군과양성자펌프억제제및 3가지항생제를 10일간투여한군을비교하였을때제균율이거의동일한것으로보고하였다. 10 기타의견으로, 대부분의연구들이 10일간의순차적제균요법과 7일간의 3제요법을비교하였으므로치료기간이긴순차적제균요법의제균율이더높다는설명이다. 이에대한반론으로최근한연구에서는 10일간의순차적제균요법과 10일간의 3제요법을비교하였을때순차적제균요법의제균율이더높게나타났다. 11

106 The Korean Journal of Helicobacter and Upper Gastrointestinal Research: 제 11 권제 2 호 2011 2. 순차적제균요법의치료성적양성자펌프억제제와 amoxicillin을 5일간투여한후추가로 5일간양성자펌프억제제와 amoxicillin 이외의 2가지항생제를사용하는전형적인 H. pylori에대한순차적제균요 법에대한연구는현재까지 30여편의논문으로발표되었는데, 그결과는 Table 1과같다. 본논고는메타분석이아니므로연구의디자인에크게제약을두지는않았고, 지역에따른분포를집중적으로살펴보고자하였다. 이표에서는당뇨병등과같은특별한질환이동반된환자에서시행 Table 2. Eradication Rates of Modified Sequential Therapy Study, year (Reference) Graham 2006 (37) Sezgin 2007 (24) Uygun 2008 (25) Molina-Infante 2010 (29) Paoluzi 2010 (21) Cetinkaya 2010 (26) Cetinkaya 2010 (26) Riahizadeh 2010 (40) Riahizadeh 2010 (40) Nadir 2011 (27) Hsu 2011 (34) Hsu 2011 (35) Country of origin Patients enrolled Centers involved Study design USA 30 1 Single branch Eso 40 mg tid Amo 1,000 mg tid Turkey 32 1 Single branch Pan 40 mg bid Turkey 150 1 RCT Pan 40 mg bid Spain 115 1 RCT Italy 90 1 RCT Eso 20 mg bid Turkey 56 1 RCT Pan 40 mg bid Turkey 56 1 RCT Pan 40 mg bid Iran 102 11 RCT Bis 240 mg bid Iran 102 11 RCT Bis 240 mg bid Turkey 144 1 RCT Lan 30 mg bid Taiwan 117 3 Single branch Eso 40 mg bid Taiwan 123 3 Single branch Eso 40 mg bid First regimen Second regimen ITT eradication Regimen Duration Regimen Duration rate (%) 5 days Eso 40 mg tid Amo 1,000 mg tid Gat 400 mg qd 7 days Pan 40 mg bid 7 days Pan 40 mg bid 5 days Lev 500 mg bid 4 days Eso 20 mg bid 5 days Pan 40 mg bid Met 500 md tid 5 days Pan 40 mg bid Met 500 md tid 5 days Bis 240 mg bid Fur 200 mg bid 5 days Bis 240 mg bid Fur 200 mg bid 7 days Lan 30 mg bid 7 days Eso 40 mg bid 7 days Eso 40 mg bid 7 days 80.0 7 days 50.0 7 days 72.6 5 days 82.5 4 days 83.0 9 days 82.1 9 days 81.5 5 days 78.5 5 days 82.0 7 days 72.2 7 days 97.4 7 days 91.9 RCT, randomized controlled trial; Eso, esomeprazole; Amo, amoxicillin; Gat, Gatifloxacin; Pan, pantoprazole; Tet, Tetracyclin; Met, metronidazole; Bis, bismuth subcitrate: Ome, omeprazole; Fur, furazolidon; Lan, lansoprazole; Cla, clarithromycin.

김종인, 김병욱 :Helicobacter pylori 의순차적제균요법 107 된연구나수술을받은환자에서의연구, 약제의용량이불명확한연구, 철분등추가투약을확인하는연구는제외하였다. 전형적인약제투여기간이나약제투여방법이아닌변형된순차적제균요법의치료성적은 Table 2와같다. 현재까지발표된논문중전형적인순차적제균요법은대부분이탈리아에서이루어진연구이며, 4,10,12-23 변형된순차적제균요법은터키에서가장많이진행되는등, 24-27 지역적으로편중되어있음을알수있다. 이탈리아에서이루어진연구는순차적제균요법의치료성적이 ITT 분석에서 80.8 98.0% 정도로보고되고있어, 4,10,12-23 이상적인 H. pylori 제균치료법으로적절한지는아직더연구가필요하다. 이탈리아이외의유럽국가에서는 ITT 분석에서 76.5 84.2% 정도로이탈리아의성적보다낮게나타나 28-30 이상적인 H. pylori 제균치료법의조건을충족하지못하고있다. 아시아에서는우리나라를비롯하여 31,32 중국, 33 대만, 10,34,35 태국 36 등에서이루어진연구로, ITT 분석에서 77.9 95.0% 로보고되는등나라마다편차가크고, 대부분의연구가후향적단일가지단일기관연구이므로조금더디자인이잘된전향적다기관연구가필요하다. 기타미국, 37 페루, 38 이스라엘, 39 이란 40 등에서산발적으로연구가이루어졌다. 3. 순차적제균요법의제균율에영향을주는요인 1) 항생제내성 : 순차적제균요법이등장한가장큰이유는 clarithromycin에대한내성균이증가하면서 H. pylori 제균율이낮아졌기때문이다. 이론적으로순차적제균요법은위에서언급한것과같이첫 5일간 amoxicillin을투여함으로써세포벽에손상을주어항생제가밖으로빠져나가지못하게되므로 clarithromycin에대한내성균도 clarithromycin에의해제균이될수있다. 그러나현재까지발표된 clarithromycin 내성균에대한순차적제균요법의제균율은 57.1 88.9% 로내성이없는균주의제균율에비해제균율이낮다 (Table 3). 41,42 아직은연구에포함된환자의숫자가많지않으므로보다더많은환자를대상으로한연구가필요하지만, clarithromycin 내성균에서도표준 3제요법에비해순차적제균요법의제균율이높게나타나므로앞으로기대해볼수있을것으로생각한다. 세계여러지역에서 metronidazole이나 tinidazole과같은 nitroimidazole계항생제에대한내성도증가하고있는것으로보고되고있으나, 43,44 순차적제균요법이이를극복할수있는지는아직확실하지않다. 현재까지 2편의논문에서 metronidazole 내성균에대한순차적제균요법의효과를표준 3제요법과비교하였는데, 11,13 통계적으로의미는없지만 metronidazole 내성균에서도순차적제균요법의제균율이표준 3제요법보다다소높게나와향후그효과를기대해볼수있을것으로생각한다. 2) 치료기간 : 순차적제균요법의기간을단축시켜제균율을그대로유지하거나, 21 기간을연장시켜 35 제균율을높이려는노력이많이이루어지고있다. 그러나, 아직까지는이러한기간의단축또는연장이제균율에크게영향을준다는보고가없어, 향후이에대한연구가더필요할것으로생각한다. 3) 기저질환 : 일부연구에서표준 3제요법은비궤양성소화불량증환자에비해소화성궤양환자에서제균율이더높다고알려져있는데, 45 Zullo 등, 46 Tong 등 47 은메타분석을통하여순차적제균요법은기저질환에크게영향을받지않는다고하였다. 4) 흡연 : Suzuki 등 48 은순차적제균요법이아닌다른제균요법으로치료하였을때, 흡연이제균율을떨어뜨린다 Table 3. Eradiation Rate of Sequential Therapy in Clarithromycin Sensitive and Resistant H. pylori Study, year (Reference) De Francesco 2006 (41) Vaira 2007 (11) Sirimontaporn 2010 (36) Mahachai 2011 (42) Country of origin Patients enrolled Italy 156 Amo 100 mg bid Italy & USA First regimen Second regimen Eraidcation rate in clarithromycin Regimen Duration Regimen Duration sensitive (%) 146 Pan 20 mg bid Thailand 115 Lan 30 mg bid Thailand 151 Lan 30 mg bid 5 days 5 days Pan 20 mg bid 5 days Lan 30 mg bid Cla 1,000 mg qd 5 days Lan 30 mg bid Cla 1,000 mg qd Eradication rate in clarithromycin resistant (%) 5 days 58/59 (98.3) 18/22 (81.8) 5 days 108/114 (94.7) 8/9 (88.9) 5 days 104/107 (97.2) 4/7 (57.1) 5 days 131/134 (97.8) 11/17 (64.7)

108 The Korean Journal of Helicobacter and Upper Gastrointestinal Research: 제 11 권제 2 호 2011 고하였으나, 순차적제균요법은흡연의영향을받지않았다. 15,46 5) 양성자펌프억제제에따른차이 : 표준 3제요법과마찬가지로순차적제균요법의제균율은양성자펌프억제제의종류에따라차이가나지않았다. 46,47 6) CagA 양성 : 일부에서는기존의제균요법이 CagA 양성일때제균율이높다고하였으나, 49 순차적제균요법은 CagA와상관이없었다. 15,46 7) 위점막에서세균의밀도 : 표준 3제요법은위점막에서세균의밀도가높을수록제균율이감소한다고하였으나, 50 순차적제균요법은위점막의세균의밀도와상관이없었다. 18 8) 나이 : 소아환자를포함하여메타분석을하면성인들만을대상으로하였을때에비하여순차적제균요법의표준 3제요법에대한 odds ratio가떨어지는것으로보아 51 제균율에나이가영향을미칠것으로생각되나, 소아환자에대한연구가아직은많지안아추가연구가필요하다. 고령자에서의연구는 1편만논문으로발표되었는데, 표준 3제요법의제균율은 80% 인데비해순차적제균요법의제균율은 94.4% 로더높은것으로나타났다. 18 9) 약물부작용 : Tong 등의메타분석에서부작용을확인할수있었던 7편의연구를분석하면표준 3제요법의부작용은 9.9%, 순차적제균요법의부작용은 9.2% 로차이가없었다. 47 또한심각한부작용으로약물투여를중단하여야하는경우는표준 3제요법의경우 0.007%, 순차적제균요법의경우 0.003% 였다. 46 10) 환자순응도 : Zullo 등 46 의메타분석에따르면순응도를확인할수있었던 8편의연구에서표준 3제요법의순응도는 94%, 순차적제균요법의순응도는 92.6% 로차이가없었다. Jafri 등 52 의메타분석에서도표준 3제요법의순응도는 96.8%, 순차적제균요법의순응도는 97.4% 로차이가없었다. 4. 순차적제균요법의제한점 1) 치료약제의복잡함 : 순차적제균요법은치료의중간에약제를바꾸어야하므로표준 3제요법보다복약방법이복잡하다. 또한표준 3제 7일요법에비해약제의개수가더많고치료기간이길어환자의순응도를떨어뜨릴수있다. 위에서언급한것과같이 Zullo 등 46 의메타분석에서는순응도의차이가없다고하였으나, 통상적으로연구에포함되는환자에비해실제임상에서만나는환자에서의순응도가더낮은점을고려할때순차적제균요법의순응도는더낮아질가능성이높다. 순응도는항생제에대한내성다음으로제균율에영향을주는요소이므로 53 이는신중 하게고려되어야할점이다. 2) 지역적제한점 : 위에서언급한것과같이순차적제균요법은대부분이탈리아에서이루어진연구이며, 이탈리아이외의나라에서 ITT 분석상 90% 이상의제균율을보인곳은대만, 10 태국, 36 이스라엘 39 뿐이다. 지역에따른항생제내성율의차이를감안하더라도보다많은환자를대상으로한여러나라에서의추가연구가이루어져야하겠다. 3) 연구대상환자수와연구의질 : Table 1에서보는것과같이 100명이하의비교적대상환자수가적은연구가많았고, Jafri 등 52 의메타분석에의하면디자인이잘된논문의표지인 Jarad 점수가대부분 3이하로낮아이역시신중하게고려해야할점이다. 향후전향적연구를통하여 PP 분석이가능한논문이더많이발표되어야하겠다. 4) 제균치료실패시대책 : H. pylori 제균요법은 1차제균요법에실패할경우를대비하여반드시적절한 2차제균요법이있어야한다. 54 그러나순차적제균요법에실패하였을경우, 짧은기간동안 3가지항생제를사용하였기때문에 2가지이상의항생제에대한내성을갖는다제내성균의출현가능성이높다. 현재까지순차적제균요법에실패한경우의대비책으로 levofloxacin을포함하는 3제요법에대한연구가있었는데, Perna 등 55 은 73% 로보고하였고, Pontone 등 56 은 7명의환자에서모두제균되었다고보고하였다. Shehada 등 57 은순차적제균요법에실패한경우 2차제균요법으로양성자펌프억제제와 bismuth제제, tetracyclin과 nitroimidazole을포함하는 4제요법의가능성을제시하였다. 5) 페니실린계항생제에대한과민반응이있는경우 : 표준 3제요법과마찬가지로페니실린계항생제에대한과민반응이있는환자에서는 amoxicillin을포함하는순차적제균요법은적합하지않다. 58 6) 비용 : 국내에서보험약가기준으로표준 3제요법으로 7일간투여할경우 pantoprazole 40 mg bid, amoxicillin 1,000 mg bid, clarithromycin 500 mg bid로약 55,300원정도이며, 순차적제균요법으로 pantoprozole 40 mg bid, amoxicillin 100 mg bid로 5일간투여후 pantoprazole 40 mg bid, clarithromycin 500 mg bid, metronidazole 500 mg bid로 5일간투여할경우약 52,800원정도이다. 5. 순차적제균요법이우리나라에서받아들여지기위해서는? 순차적제균요법은미국소화기학회와 59 유럽에서 60 표준 3제요법을대체할수있는 1차제균치료법으로가능성을인정하고있어이를국내에서받아들이기위해서는우리나라에서의순차적제균요법의제균율에대한정확한데이터가필요하다. 그러나현재까지우리나라에서이루어

김종인, 김병욱 :Helicobacter pylori 의순차적제균요법 109 진연구는단 2편의논문에불과하며, 이중 1편은후향적연구이고기타초록으로발표된연구들도있다. 표준 3제요법을대체하기위한 1차제균요법으로서순차적제균요법을받아들이기위해서는현재사용중인표준 3제요법의제균율이우리나라의권고안으로받아들일수없을정도로낮아졌는지에대한정확한데이터가필요하다. 또한순차적제균요법의근본원리가 clarithromycin 내성균에있으므로이에대한연구도지속적으로이루어져야하겠다. 결 순차적제균요법은이탈리아를중심으로여러나라에서연구가진행중이다. 현재까지의연구결과를종합하면표준 3제요법에비해제균율이높은것으로나타나고, clarithromycin에대한내성균에서도표준 3제요법보다높은제균율을보이는것으로생각된다. 그러나제균율은지역에따른편차가심하고, 제균실패시필요한 2차제균요법이아직명확하게확립되어있지않아보다더많은연구가필요할것으로생각한다. 국내에서이요법을받아들이기위해서는대한상부위장관ㆍ헬리코박터학회가중심이되어전향적다기관연구와 clarithromycin에대한내성률에관련된연구가이루어져야하겠다. 론 참고문헌 1. Kim N, Kim JJ, Choe YH, Kim HS, Kim JI, Chung IS; Korean College of Helicobacter and Upper Gastrointestinal Research; Korean Association of Gastroenterology. Diagnosis and treatment guidelines for Helicobacter pylori infection in Korea. Korean J Gastroenterol 2009;54:269-278. 2. Kim BW, Choi MG, Moon SB, et al. Pooled analysis of antibiotic therapy for Helicobacter pylori eradication in Korea. Korean J Gastroenterol 1999;34:42-49. 3. 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