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1 Korean J Gastroenterol Vol. 63 No. 3, pissn eissn REVIEW ARTICLE 헬리코박터제균치료의미래 이주엽 1, 김나영 1,2 분당서울대학교병원내과 1, 서울대학교의과대학내과학교실간연구소 2 Future Trends of Helicobacter pylori Eradication Therapy in Korea Ju Yup Lee 1 and Nayoung Kim 1,2 Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam 1, Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul 2, Korea The prevalence of Helicobacter pylori infection in Korea shows a decreasing trend and has changed to that of developed country, especially for those below 30 years old. However, the primary antibiotic resistance rates are higher than those of developed countries. The reason for the decrease in the efficacy of standard triple therapy is mainly due to the increase in the resistance against clarithromycin. Sequential therapy seems to be more effective than the standard triple therapy, but the intention-to-treat eradication rate of sequential therapy in Korea, which is mostly under 80.0%, is still not satisfactory. Therefore, a promising regimen is needed. Recently, the Japanese health insurance system admitted H. pylori-infected gastritis as an indication of eradication. Furthermore, the Kyoto Consensus Meeting on H. pylori Gastritis held from January 30th to February 1st, 2014, proposed that all H. pylori positive patients should be offered to receive H. pylori eradication. This suggests that the concept of eradication has been changed from treatment to prevention. Various individualized tailored therapy based on the polymorphism, age and other demographic factors and antibiotic resistance has been attempted to maximize H. pylori eradication therapy. The aim of this article is to review the current epidemiology, H. pylori resistance state, treatment guideline, and to assess the possible future strategy and treatment for H. pylori infection in Korea. (Korean J Gastroenterol 2014;63: ) Key Words: Helicobacter pylori; Guidelines; Treatment; Prevention 서론 Helicobacter pylori는그람음성막대균으로사람의위점막에장기간기생하면서만성위염, 소화성궤양, 위변연부 B 세포림프종, 그리고위암을일으킨다. 1,2 1982년배양에성공하면서위점막에서식하는세균으로인정받은후, 여러후속연구들을통하여역학적특성과병태생리, 그리고진단과치료방법등에괄목할만한진전이이루어졌다. H. pylori 감염의치료는소화성궤양의재발을억제하고, 위변연부 B세포림프종의관해를유도하며, 조기위암의내시경치료후재발 률을낮출수있는것으로알려져있으며, 3,4 국내에서는프로톤펌프억제제 (proton-pump inhibitor, PPI) 를포함한표준삼제요법을 1차치료로사용하여왔으나 5 점점증가하고있는항생제내성으로인해그효과가감소하고있다 년 1월 30일부터 2월 1일에열린 Kyoto Consensus Meeting에서는 H. pylori 제균치료가위암예방효과가있으며, 모든 H. pylori 감염환자에서제균치료를권유하는방안을담고있다. 이는기존의치료적개념에서예방적개념의제균치료로변화를뜻하며, 젊은층을중심으로점차 H. pylori 감염률이떨어지고있는우리나라에서도이러한추세에발맞추어제균 CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 교신저자 : 김나영, , 성남시분당구구미로 173번길 82, 분당서울대학교병원내과 Correspondence to: Nayoung Kim, Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-ro, 173beon-gil, Bundang-gu, Seongnam , Korea. Tel: , Fax: , nayoungkim49@empas.com Financial support: This work was supported by a grant from the National Research Foundation of Korea funded by the Korean Government (2012R1A1B ). Conflict of interest: None. Korean J Gastroenterol, Vol. 63 No. 3, March

2 Lee JY and Kim N. Future H. pylori Eradication Therapy 159 치료의적응증을넓히기위해서는기존의제균요법에대한재검토및새로운제균치료에대한논의가필요하다고본다. 이에본고에서는 H. pylori의역학, 내성증가현황에대해서알아보고최근가이드라인의변화및최근대안으로제시되고있는다양한치료법을정리함으로써앞으로의바람직한방향에대해논의해보고자한다. 본론 1. 역학전세계적으로 H. pylori 감염률은성인인구에서 50% 이상이며, 감염빈도는선진국일수록낮고개발도상국이나저개발국에서높고, 성별, 연령, 지역적분포, 종족간에도차이를보인다. 7 미국이나유럽과같은선진국에서의 H. pylori 유병률은 3-5세에 10-15% 였다가연령이높아지면서증가하지만, 인도나사우디아라비아와같은개발도상국이나저개발국의경우에는 10세이전에 40-60% 의높은유병률을나타내며, 8,9 이는성장기의사회경제여건의중요성을뒷받침해주고있다. 같은지역에서도인종간의차이를보여라틴아메리카계미국인의경우유병률이 80% 정도로높고, 무증상아프리카계미국인의경우백인과비교했을때연령별 H. pylori 감염률의증가는비슷하나유병률자체는훨씬높다. 또한흑인계및히스패닉 (Hispanic) 계미국인들의경우 H. pylori 유병률이사회경제적요소를보정한후에도백인들보다 2배가높은데, 10,11 이러한높은유병률은성장기의열악한사회경제적여건에기인하는것으로밝혀져 12,13 가족수, 감염된가족구성원유무, 개인위생상태및사회경제적인자가 H. pylori 유병률결정에중요한요소로생각되고있다. 중국과우리나라, 그리고일본의 H. pylori 유병률을비교해보면, 중국의장쑤성일대농촌지역의경우전연령에서감염률이 55% 이상으로나타났으며, 14 수도베이징일대의감염률은이보다낮기는하지만역시전연령에서비슷한감염률을보여, 15 아동기에 H. pylori 감염률이높은전형적인개발도상국의유형을보이고있다 (Fig. 1A). 우리나라에서는 1998년대한 H. pylori 연구회에서총 5,732명의제균력이없는무증상인구를대상으로전국적인역학조사를시행한결과, 16세이상성인에서의혈청유병률은 66.9% 였고, 영유아포함 15세이하에서는평균 17.2% 로나타났다. 16 전국건강검진자 15,916명을대상으로한 2005년연구에서는 16세이상제균력이없는무증상성인에서의혈청유병률은 59.6% 로 1998년에비하여감소하였으며, 17 역시같은조건의 2011년 16세이상 10,796명의무증상의건강검진수진자혈청유병률은 54.4% 로 1998년및 2005년과비교하여볼때유의하게감소하는추세였다. 18 또한, 나이에따른유병률조사에서도모든연령에서감소하는추세를보였으며, 특히 40세미만의연령에서감염률이큰폭으로감소한바있다 (Fig. 1B). 18 일본의경우우리나라보다일찍선진국형으로바뀌었는데, 2007 년에서 2011년의조사에서는유아기의 H. pylori 감염률은낮고이후점점증가하여 60대이후로는 50% 중반에이르는그래프를보이고있으며, 이전조사에비해서감염률은점점감소하고있는추세이다 (Fig. 1C) 이상에서살펴본바와같이전반적인사회경제적요인과위생상태의개선에따라우리나라도개발도상국의감염형태에서선진국형으로이행하는단계임을알수있으며, cohort 효과로인해향후 40대이후에서도 H. pylori 유병률은점점감소하는양상을보일것으로기대된다. Fig. 1. Comparison of prevalence rate of Helicobacter pylori infection among China, Korea, and Japan. (A) Prevalence (using urea breath test or serum IgG antibody) by age in in Jiangsu, China and in 2003 in Beijing, China. 14,15 (B) Seroprevalence in asymptomatic subjects without a history of H. pylori eradication in 1998, 2005, and 2011 in Korea (C) Prevalence (using urine antibody or serum IgG antibody) of H. pylori in 1992, , and in Japan Reused from the article of Shiota, et al. (Expert Rev Gastroenterol Hepatol 2013;7:35-40) 21 with original copyright holder s permission. Vol. 63 No. 3, March 2014

3 160 이주엽, 김나영. 헬리코박터제균치료의미래 Table 1. Antibiotics Resistance Rates (%) for Helicobacter pylori Infection around the World Antibiotics USA ( ) 29 Europe ( ) 30 Northern Central/Western Southern Japan ( ) 28 China ( ) 41 Amoxicillin 0.9 <0.7 <0.7 < Clarithromycin Metronidazole Tetracycline - <0.9 <0.9 < Ciprofloxacin Levofloxacin Table 2. Antibiotic Resistance Rates for Helicobacter pylori in Korea Seoul Gyeonggi Gyeonggi Gangwon Busan Antibiotics (n=34) (n=36) (n=63) (n=130) (n=129) (n=69) (n=65) (n=65) (n=69) (n=202) (n=204) (n=40) (n=40) (n=19) Amoxicillin Clarithromycin Metronidazole Tetracycline Ciprofloxacin Levofloxacin Moxifloxacin Resistant breakpoints of minimum inhibitory concentration (MIC) were defined as 0.5 mg/ml for amoxicillin, 1.0 mg/ml for clarithromycin, 8.0 mg/ml for metronidazole, 4.0 mg/ml for tetracycline, 1.0 mg/ml for ciprofloxacin, levofloxacin and moxifloxacin. Values represent percent numbers (patients infected with resistant H. pylori/total subjects). 2. H. pylori 치료의내성증가현황 H. pylori 치료에있어서가장중요한항생제는 clarithromycin, metronidazole, amoxicillin이며이항생제들에대한내성증가가제균치료실패의중요한원인으로작용하고있다 현재까지가장널리사용되어온 PPI에 amoxicillin과 clarithromycin을병합한표준삼제요법의제균율은전세계적으로감소하고있는추세이며, clarithromycin 내성이제균실패의주요원인이다. 지역적인차이는있으나이미미국과유럽, 아시아의선진국에서 20% 이상의높은 clarithromycin 내성률을보이는지역이많지만, 유럽에서도중부유럽, 서유럽, 남유럽에서는 clarithromycin 내성이 20% 를넘고있으나북유럽은 10% 미만으로그내성이낮았다 (Table 1). 27 일본의다기관조사에서도 2002년의 clarithromycin 내성률은 18.9% 인데반해 2006년의 clarithromycin 내성률은 27.2% 로급격히증가함을보고하였다. 28 미국과유럽의 metronidazole 내성률은 20-40% 정도이고 29,30 일본의 metronidazole 내성률은 % 이지만, 28 아시아의일부지역과아프리카, 그리고남아메리카지역에서는 metronidazole 내성률이 80% 가넘는지역도있다 또한 quinolone 내성도유럽과아시아의선진국에서점차증가하 는것으로보고되고있으며, 30,34 amoxicillin 내성률은유럽에서는 2% 미만으로보고되고있으나 30,35,36 아프리카와아시아, 그리고라틴아메리카지역에서는 6-59% 로보고되고있다. 37,38 Tetracycline의내성률은대부분의나라에서 5% 미만으로보고되고있으나 (Table 1), 일부아시아와라틴아메리카에서는 9-27% 까지보고되고있다. 30,39-41 이러한차이는항생제사용패턴에따른지역적차이겠지만경우에따라서는 agar dilution법내지 E-test와같은항생제내성검사방법의차이에기인했을가능성을배제할수없다. 2000년이후세계적항생제내성률보고및한국에서보고된 H. pylori 일차항생제내성률을살펴보면, clarithromycin 내성률 20% 이상, metronidazole 내성률 40% 이상, 그리고 quinolone 내성률 10% 이상으로한국은항생제내성의문제가심각한국가중하나이다. 39 국내 clarithromycin 내성률을자세히살펴보면 (Table 2), 1987년한양대학교병원과서울대학교병원에서분리한균주에서 0% 와 1994년 2.8% 로낮았으나 2003년에는 13.8% 로급격히증가하였다 년개원한분당서울대병원에서분리된균주의내성률은 2003년부터 2005년까지 23.2%, 2006년부터 2008년까지 27.2%, 2009년에서 2013년까지 37.3% 로급격한상승을보이고있다. 6,43 Metronidazole 내성률은한양대학교병원과서울대학교병원 The Korean Journal of Gastroenterology

4 Lee JY and Kim N. Future H. pylori Eradication Therapy 161 Table 3. Treatment Indication and Recommended First-line Regimen against Helicobacter pylori Infection by Japanese, Korean, and European Guideline Japan (2009 revised edition) 47 Korea (2013 revised edition) 48 Europe (Maastricht IV, 2012) 49 Indication H. pylori infection (Recommendation grade A) Evidence level A Gastroduodenal diseases Evidence level I 1) Peptic ulcer disease (1A) Peptic ulcer disease 1) Peptic ulcer disease 2) MALToma (1A) MALToma 2) Atrophic gastritis 3) Following EMR for EGC (1A) Following EMR for EGC 3) Idiopathic thromcobytopenic purpura 4) Idiopathic thromcobytopenic purpura Gastritis with preneoplastic conditions 4) Functional dyspepsia (1A) Functional dyspepsia Evidence level II 1) Following EMR for EGC 5) Functional dyspepsia (2A) Evidence level B Prior to NSAIDs therapy/additional to PPI therapy 2) Gastric hyperplastic polyps 1) First-relatives of gastric cancer (2B) In Aspirin users with history of 3) Reflux esophagitis Evidence level C peptic ulcer Evidence level III 1) Atrophic gastritis/intestinal In patients on long term PPI 1) Iron-deficiency anemia metaplasia (2C) Extragastric diseases 2) Chronic urticaria 2) Long-term use of low dose Idiopathic thrombocytopenic purpura 3) MALToma aspirin (2C) Iron deficiency anemia Vitamin B12 deficiency First-line regimen PPI (standard dose b.i.d.) Clarithromycin ( mg b.i.d) Amoxicillin (750 mg b.i.d.) PPI (standard dose b.i.d.) Clarithromycin (500 mg b.i.d) Amoxicillin (1,000 mg b.i.d.) Duration 7 days 7-14 days 7 or days Prevalence of Clari-R <20%: PPI-Clariamoxicillin/metronidazole Prevalence of Clari-R >20%: bismuth quadruple therapy or sequential/ concomitant therapy EMR, endoscopic mucosal resection; EGC, early gastric cancer; MALToma, mucosal associated lymphoid tissue lymphoma; PPI, proton pump inhibitor; Clari-R, clarithromycin resistance; b.i.d., bis in die (twice a day). In Japan guideline 47 : Recommendation grade A, strongly recommended based on strong evidence; Evidence level I, systemic review/ meta-analysis; level II, at least one randomized controlled clinical trial; level III, non-randomizedcontrolled clinical studies. In Korea guideline 48 : Evidence level A, high-quality evidence; level B, moderate-quality evidence; level C, low-quality evidence; strength of recommendation 1, strong; strength of recommendation 2, weak. 에서분리한균주에서 1987년 52.9%, 1994년 61.1%, 2003년 66.2% 로매우높았으며, 42 삼성서울병원에서분리한균주에서의내성률도 1994년 33.3% 에서 1999년 47.7% 로꾸준히증가하는양상을보였다. 44 분당서울대학교병원의 metronidazole 내성률은 년에 34.8% 로비교적낮은편이고 년에 23.8% 로더감소하는추세를보이다가 년까지는 35.8% 로다시증가하는양상을보였다. 43 Quinolone 계열항생제 (ciprofloxacin, levofloxacin, moxifloxacin) 의내성률은서울대학교병원분리균주에서 1987년 0%, 1994년 13.9%, 2003년 33.8% 로급격히증가하였으며, 42 이러한급격한증가추세는분당서울대학교병원분리균주에서도마찬가지로확인할수있었다 년시행한경기, 강원, 부산지역의항생제내성률비교분석을보면 clarithromycin 내성률은경기에서 32.5%, 부산에서 26.3% 로높았으나강원지역에서는 12.5% 로낮았으며, metronidazole 내성률역시강원지역에서는 10.0% 로낮았다. 하지만, quinolone 계열항생제의내성률은세지역모두에서 20% 이상으로높게측정되었다. 45 두가지이상의약제에내성을보이는다약제내성균주는 1987년 24%, 1994년 33%, 2003년 47.7% 로시간이지남에따라증가하고있다. 42,46 이상에서살 펴본바와같이국내에서항생제내성 H. pylori 균주는지속적으로증가하고있는추세이며, 다약제내성균주도증가하고있는추세이다. 한기관에서 agar dilution법으로진행된경기, 강원, 부산지역의항생제내성률의차이는아마도지역차이라기보다는항생제사용패턴의차이와각병원의중증도차이의반영일수있겠으나제균치료의지침을지역적으로달리적용할필요를시사하는결과라하겠다. 3. 최근가이드라인의변화세계각국가, 지역마다 H. pylori의적절한치료를위해지역적특성을고려한진단및치료지침을제정하고있다 (Table 3) 본고에서는최근 H. pylori 치료전략에있어서큰변화를가져온유럽가이드라인 49 및제균치료대상의변화를가져온일본가이드라인, 47 그리고가장최근인 2014년 1월 30일에서 2월 1일사이에열린 Kyoto Global Consensus Meeting에대해살펴보고자한다. 1) Maastricht IV Consensus Report (2012년) 2012년에발표된 Maastricht IV Consensus Report에서는치료전략에있어서 clarithromycin 내성을고려한것이특징이다. Clarithromycin 내성률 20% 를기준으로내성이낮은 Vol. 63 No. 3, March 2014

5 162 이주엽, 김나영. 헬리코박터제균치료의미래 지역과높은지역으로구분하였는데, 내성이낮은지역에서는 clarithromycin을포함한삼제요법이경험적 1차치료로권장되고 bismuth 사제요법이대안이될수있으며, 치료에실패한경우 bismuth 사제요법이나 levofloxacin을포함한삼제요법을 2차치료로권장하고있다. 반면, 내성이높은지역에서는 bismuth 사제요법을경험적 1차치료로권장하고있으며, 순차치료 (sequential therapy) 혹은동시치료 (concomitant therapy) 를 1차치료로권장하고있다. 순차치료혹은연속치료는비록 clarithromycin을포함하고있으나기존발표들에의하면치료성공률이약 75-95% 정도되므로 clarithromycin 내성을어느정도극복할수있는것으로평가하고있다. Clarithromycin 내성이높은지역에서순차치료로의 1차치료에실패하게되면 levofloxacin을포함한삼제요법이 2차치료로권장되고있다. Clarithromycin 내성에관계없이 2차치료에실패하게되면, 배양및항생제감수성검사를시행한후 3차치료를진행하기를권장하고있다. 즉, 항생제내성률에따라치료전략을달리해야함을강조하고있는것이다. 2) 제균치료대상의최근변화 - 일본 (2013년 2월 ) 2009년개정된일본 H. pylori 치료가이드라인에서는 H. pylori 감염이있을경우이와연관된질병이없더라도제균치료를할것을강력히권고하였다 (Recommendation grade A). 47 일본의약절반정도의인구가 H. pylori에감염되어있으며, H. pylori에감염된인구는비록위축성위염, 소화성궤양, 위암, 위변연부 B세포림프종등의질병이없더라도이러한 H. pylori와연관된질병이발생될위험이높기때문에이를예방하기위해서, 또는 H. pylori 균의전파를막기위한예방적차원에서제균치료를시행하자는개념인데, 제균에성공하게되면위염의조직학적소견의호전은물론소화성궤양과위암의발생을막을수있다는연구에기초한것이었다 이러한일본가이드라인변화에도불구하고 H. pylori 감염의제균치료에대해서최근까지보험적용을하지않던일본정부가 2013년 2월부터기존의적응증이었던 (1) 소화성궤양, (2) 위변연부 B세포림프종, (3) 조기위암의내시경적절제후, (4) 특발성혈소판감소성자반증의네가지질환적응증에이어내시경으로진단된 (5) H. pylori 감염성위염 (H. pylori infected gastritis) 이면모두제균치료를보험적용되게함으로써세계적인관심을모으고있다. 일본의체계적문헌고찰에서는 H. pylori 제균치료는위암의유병률을약 1/3 가량감소시키는것으로보고한바있으며, 56 제균치료후 10년동안전향적으로경과관찰을한연구들에서는성공적제균치료는조직학적염증이나위축을유의하게호전시키는것으로보고하고있다. 57,58 하지만위험요소에무관하게 H. pylori에감염된모든사람을대상으로한제균치료 (mass eradication) 가위암을예방할수있는가를입증하려면잘고안된연구가필요한데, 59,60 이는많은수의참가자를대상으로오랜기간동안관찰이필요하기때문에결코쉽지않다. 이러한어려움에도불구하고최근위암의유병률이높은아시아에서 H. pylori 제균치료의위암예방효과에대한대규모연구들이시행되어긍정적결과를제시하고있다. 즉, 대만에서 2004년에서 2008년사이 30세이상 H. pylori에감염된 5,000 명의참가자를대상으로제균치료를시행하였고, 제균치료를시행하지않은 1995년에서 2003년사이의결과와비교하여제균치료의위암예방효과에대해발표함으로써세계적주목을받은바있다. 61 즉, 제균치료후 H. pylori의감염률은 78.7%, 위축성위염은 77.2% 에서감소하였으며, 위암발생률은 25% 감소한결과를보였다. 61 중국에서시행된또다른연구에서는 H. pylori 혈청검사양성인 2,258명을제균치료군과위약군으로나누어서 15년관찰한결과제균치료를시행한군에서위약군보다위암의발생률이 39% 감소된결과를보였다. 62 제균시기가중요한데, Asaka 등 63,64 은 40세이전에는위축성위염의유병률이낮기때문에 H. pylori 제균치료를시행할경우거의 100% 에가까운위암예방효과를가져올수있는반면, 50세이상에서는위축성위염의빈도가높기때문에제균치료를시행하더라도나이가들수록위암발생가능성이높아지므로제균치료를시행한후에도위축성위염의유무와그정도에따라정기적인내시경검사를시행해야한다고보고하였다. Wu 등 65 은대만에서약 80,000명의소화성궤양환자를제균치료하고 10년동안관찰하였는데, H. pylori 진단즉시제균치료를시행한군은 H. pylori 진단 1년후에제균치료를시행한군에비해위암의발생률이유의하게낮음을보고하였다. 일본 H. pylori 가이드라인및최근보험적용내용의변화는비록예방적제균치료에따르는문제점을감수하고서라도연간위암사망인구가 50,000명에달하는일본에서 H. pylori 에감염된위를가역적인단계에서조기에구제하여궁극적으로위암이없는일본을후세들에게물려주고자하는강한의지가담겨져있는바, 64,66 일본과함께위암유병률이높은우리나라에서도이를주목할필요가있겠다. 3) The Kyoto Global Consensus Meeting on H. pylori Gastritis (2014년 1월 30일-2월 1일 ) 2014년 1월 30일부터 2월 1일까지 Graham, Kuipers, Malfertheiner 등전세계에서 22명, 그리고일본에서 24명의저명한학자들이 Kyoto에모여 H. pylori gastritis에대한 Global Consensus Meeting을가졌다. 총 4개의세션 ( 위염의분류, H. pylori와연관된소화불량, 위염의진단, 위염의치료 ) 으로나누어 23개 (CQ1-23) 의질문에대한 statement를제정하였는데, 주요내용들은다음과같이요약할수있겠다. The Korean Journal of Gastroenterology

6 Lee JY and Kim N. Future H. pylori Eradication Therapy 163 첫째, 위염의분류에있어서주된내용은 H. pylori 위염을 감염성질환 으로정의한것이다. 비록환자의증상이없고, 소화성궤양이나위암등에관련된질환이없더라도 H. pylori 위염자체를감염성질환으로보아야하며, 질병분류에있어서도 H. pylori를하나의원인인자로간주해야한다는것이다. 여기에더하여위염의위치에따라, 그리고위염의조직학적소견에따라세분화하는것이필요하다고주장하고있다. 둘째, H. pylori와연관된소화불량증에서 H. pylori 위염이소화불량을일으키는하나의원인인것으로규정하고있다. 이에더나가소화불량증상호전에있어제균치료가위약 (placebo군) 및다른치료보다효과가좋으므로 H. pylori 감염양성인소화불량증의경우제균치료를 1차치료로추천하고있다. 셋째, 위염의진단에있어서 Update Sydney System은위염의조직학적진단에는적합하지만위축을평가하기위해서는개선이필요하며, OLGA (operative link on gastritis assessment) 와 OLGIM (operative link on gastric intestinal metaplasia assessment) 은위암의위험도예측에유용하다고하고있다. 또한, 위축성위염과장상피화생의진단은 narrow band imaging-확대내시경등의신기술로그진단율을높일수있으며, 혈청학적표지자인 pepsinogen I, II 그리고 anti-h. pylori antibody는위암의고위험군을선정하는데유용하다고하고있다. 그리고위축성위염과장상피 화생이발생하기이전의나이에서 H. pylori 위염에대한스크리닝을시행할것을강조하고있다. 넷째, 위염의치료에서가장핵심적인내용은모든 H. pylori 양성환자는제균치료를시행하자는것인데, 의사는 H. pylori 감염이확인되면환자에게이사실을알리고제균치료의필요성을알려주어야 (offer) 한다는것이다. 또한제균치료는위암을예방할수있지만, 제균치료를시행한다고해서위암의위험요소가제거되는것은아니므로 50세이상, 위축성위염의정도가심하거나장상피화생등의위암발생의위험요소가있을경우정기적인위내시경검사를추천하고있다. Time for a Change 를모토로내건 Kyoto Global Consensus Meeting은진단및치료에있어서많은급진적변화를제시하고있으며, 특히소화불량증환자에서제균치료의필요성을강조한다거나, 위암의예방을위해모든 H. pylori 감염환자를제균치료의대상으로하고있다는점에서우리나라에서이에대한더많은연구가필요함을느끼게해준다. 4. 1차치료의대안은무엇인가? 1) 표준삼제요법의실패적합한 H. pylori 제균치료법으로는 per protocol analysis (PP 분석 ) 에서 90% 이상, intention-to-treat analysis (ITT 분석 ) 에서 80% 이상치료성공률이있어야하며부작용이 5% Table 4. Current Recommended Regimens against Helicobacter pylori Infection Treatment Regimen First-line therapy Standard triple therapy PPI (standard dose, b.i.d.), clarithromycin (500 mg, b.i.d.), amoxicillin (1 g, b.i.d.) for 7-14 days Bismuth quadruple therapy PPI (standard dose, b.i.d.), bismuth (standard dose, q.i.d.), tetracycline (500 mg, q.i.d.), metronidazole (250 mg, q.i.d.) for days PPI (standard dose, b.i.d.), bismuth (standard dose, q.i.d.), tetracycline (500 mg, q.i.d.), amoxicillin (1,000 mg, t.i.d.) for 14 days Sequential therapy Day 1-5: PPI (standard dose, b.i.d.), amoxicillin (1 g, b.i.d.) Day 6-10: PPI (standard dose, b.i.d.), clarithromycin (500 mg, b.i.d.), metronidazole (500 mg, b.i.d.) Concomitant therapy PPI (standard dose, b.i.d.), clarithromycin (500 mg, b.i.d.), amoxicillin (1 g, b.i.d.), metronidazole (500 mg, b.i.d.) for 7-10 days Hybrid therapy Day 1-7: PPI (standard dose, b.i.d.), amoxicillin (1 g, b.i.d) Day 8-14: PPI (standard dose, b.i.d.), amoxicillin (1 g, b.i.d.), clarithromycin (500 mg, b.i.d.), metronidazole (500 mg, b.i.d.) Second-line therapy Bismuth quadruple therapy PPI (standard dose, b.i.d.), bismuth (standard dose, q.i.d.), tetracycline (500 mg, q.i.d.), metronidazole (500 mg, q.i.d.) for days Levofloxacin triple therapy PPI (standard dose, b.i.d.), levofloxacin (500 mg, q.d.), amoxicillin (1 g, b.i.d.) for 10 days Moxifloxacin triple therapy PPI (standard dose, b.i.d.), moxifloxacin (400 mg, q.d.), amoxicillin (1 g, b.i.d.) for 10 days Third-line therapy Culture-guided therapy 10-day quadruple therapy: PPI (standard dose, b.i.d.), bismuth (standard dose, q.i.d.), two antibiotics selected by antimicrobial sensitivity tests Levofloxacin quadruple therapy PPI (standard dose, b.i.d.), bismuth (standard dose, q.i.d.), levofloxacin (500 mg, q.d.), amoxicillin (500 mg, q.i.d.) for 10 days Rifabutin-based triple therapy PPI (standard dose, b.i.d.), rifabutin (150 mg, b.i.d.), amoxicillin (1 g, b.i.d.) for 14 days PPI, proton pump inhibitor; b.i.d., bis in die (twice a day); q.i.d., quater in die (4 times a day); t.i.d., ter in die (3 times a day); q.d., quaque die (once a day). Vol. 63 No. 3, March 2014

7 164 이주엽, 김나영. 헬리코박터제균치료의미래 Table 5. Summary of Meta-analysis Investigating the Efficacy of Sequential therapy Compared with Standard Triple Therapy First author Study years RCT (n) Patient (n) Region Overall eradication rate (ITT, %) Relative risk (95% CI) SQT STT vs. STT vs. 7-day STT vs. 10-day STT vs. 14-day STT Jafri ,747 Italy ( ) 1.26 ( ) 1.35 ( ) - Gatta ,006 Italy ( ) 3.21 ( ) 2.93 ( ) - Tong ,883 Italy ( ) 1.16 ( ) - Gatta ,666 Global ( ) 1.11 ( ) 1.00 ( ) Yoon ,419 Asia ( ) 1.15 ( ) 1.05 ( ) 1.06 ( ) Kim ,759 Korea ( ) RCT, randomized controlled trial; ITT, intention-to-treat; SQT, sequential therapy; STT, standard triple therapy. 이하, 가급적 1주일간의치료기간이바람직하다고권유되어왔다. 2,67,68 이에맞추어현재까지가장널리사용된 H. pylori 제균요법은 PPI에 2개의항생제 (amoxicillin, clarithromycin) 를추가하는표준삼제요법이었다. 이요법의제균율은초창기에는효과적인것으로인정받았지만항생제내성률의증가와함께그제균율이감소하여메타분석을포함한국내외의보고를종합해보면 18% 정도만이 ITT 분석에서제균율 85% 를넘을뿐, 60% 에서는 ITT 분석에서제균율이 80% 에미치지못한다고한다. 69 이미서구에서는표준삼제요법을 legacy therapy 로간주하고있으며, 유럽가이드라인에서도 clarithromycin 내성이 20% 미만일때만 1차치료로권장하고있다. 표준삼제요법의실패의대안으로 PPI와세가지의항생제를사용하는다양한형태의치료가시행되고있는데, 대표적으로순차치료, 동시치료, 변형순차치료를들수있겠다 (Table 4). 2) 순차치료, 동시치료는적절한대안이될수있을까? 순차치료 (sequential therapy) 는 5일간 PPI와 amoxicillin 을투약하고, 이후나머지 5일간 clarithromycin과 metronidazole 혹은 tinidazole을투약하는것이다. 2000년 Zullo 등 70 이처음소개하면서그제균율이 ITT 분석에서 98% (95% CI, ) 에이른다고보고하였다. 순차치료의이론적근거는첫 5일간 amoxicillin을투여하면 H. pylori 균주의세포벽이손상되어 clarithromycin과같은항생제가균주안으로침투하기쉬워지고, 세포벽이손상된 H. pylori 균주는 clarithromycin을밖으로내보내는채널이형성되지않아 clarithromycin에대한내성이발생하더라도항생제의효과가그대로유지되어제균효과를높인다는것이다. 이탈리아에서시행된 2008년이전의무작위대조연구를기반으로한 3개의메타분석결과에의하면 ITT 분석에서순차치료의제균율은 % 로표준삼제요법의 % 에비해서유의하게높았다 (Table 5) 년이후에유럽 ( 이탈리아, 스페인 ) 에서시행된무작위배정연구에서순차치료의제균율은 ITT 분석에서대부분 80% 를넘고있으며, 비록초창기보다 제균율이조금감소한면은있으나여전히표준삼제요법에비해우월한제균율을보이고있다 여섯개의무작위배정전향적연구를기반으로국내에서진행한메타분석결과에의하면순차치료의제균율은 ITT 분석에서 79.4%, PP 분석에서 86.4% 였으며, ITT 분석에서상대위험도 (relative risk) 는 1.761로순차치료가표준삼제요법보다우수함을입증하였다 (Table 5). 81 하지만, 비록표준삼제요법에비해서우월한제균율을보였지만한국에서의순차치료의제균율은기대만큼높지않았으며 (ITT, 79.4%; 95% CI, ) (Fig. 2), 81 한국을포함한아시아지역에서도마찬가지결과를보였는데, 82 초창기의이탈리아의결과와비교해보면약 10% 정도낮은수치이다. 이는한국을포함한아시아지역의 H. pylori 항생제내성의지역적특성으로설명할수있겠다. 이탈리아지역의 clarithromycin과 metronidazole의동시내성은 % 에불과한반면, 83,84 한국은 9.6%, 85 중국은 20.5%, 41 이란은 44.7%, 86 인도는 47.0% 87 로상대적으로높은비율을보이고있는것이특징이다. 각각의항생제내성의유병률과각항생제의제균성공률을이용하여전체투약요법의예측된제균율을계산할수있는데, 이계산에따르면 clarithromycin 내성이있으며 10일순차치료의 PP 제균율은 80%, metronidazole 내성이있으며 10일순차치료의 PP 제균율은 75% 로예상된다고한다. 88 Clarithromycin과 metronidazole의동시내성이있을경우는치료실패의가능성이더높아지는데, 동시내성이 5% 를초과할경우 14일순차치료의 PP 제균율은 90% 미만으로감소한다고한다. 88 동시치료 (concomitant) 는 bismuth 비포함사제요법 (nonbismuth quadruple therapy) 이라고도불리는데, PPI와 amoxicillin, clarithromycin, metronidazole을동시에투약하는것이다. 2000년초반까지의연구를기반으로두개의메타분석의 ITT 분석에서제균율은 90% 정도로표준삼제요법에비해우수한결과를보였으며, 89,90 최근에시행된 2011 년까지의 15개의연구 1,723명의환자를대상으로한메타분석에서도제균율은 ITT 분석에서 90% 로표준삼제요법보다 The Korean Journal of Gastroenterology

8 Lee JY and Kim N. Future H. pylori Eradication Therapy 맞춤형치료 (tailored therapy) 로가는길 Fig. 2. The mean intention-to-treat (ITT) eradication rate for sequential therapy reported after 2008 in Europe (Italy, Spain 78,79 ), Korea, 82 and Asia (China, Taiwan, India, and Iran). 82 높은결과를보였다. 91 최근시행된국내의한연구에서는동시치료의제균율은 ITT 분석에서 80.7% 로표준삼제요법제균율 72.6% 에비해높았으나통계적차이는없었고, 경미한부작용은동시요법 (35.6%) 에서표준삼제요법 (25.2%) 보다더많은경향을보였다. 92 순차치료와동등한치료효과를보이고있으나 77,79 부작용은좀더빈번하다는보고가있다. 77 하지만, metronidazole 내성이있을경우동시치료의효과에대해서는아직까지데이터가부족한실정이며, clarithromycin과 metronidazole의동시내성이 15% 를초과할경우 PP 제균율은 90% 미만으로감소하게된다. 88 변형순차치료 (hybrid therapy) 는 PPI와 amoxicillin을 14일간투여하고후반 7일에 clarithromycin과 metronidazole을추가하는방법으로순차치료와동시치료를병합해놓은방법이다. 93,94 비록복용방법이복잡하기는하지만 14일동시요법과비교하여서효과가동등하다는보고가있으나, 95 아직까지관련보고가적어서추가적인연구가필요한실정이다. 순차, 동시치료와마찬가지로 clarithromycin과 metronidazole 동시내성이 9% 를초과할경우제균율은 90% 미만으로감소한다. 88 전술한바와같이우리나라의 clarithromycin과 metronidazole의내성은 30% 를넘고동시내성도 10% 정도이므로순차치료와동시치료의예상제균성공률은기대에미치지못할것으로생각되며, 이미시행된순차치료에대한메타분석에서도 6개중 5개연구에서 ITT 제균율이 80% 미만이었다 (Fig. 2). 무엇보다도항생제내성을극복하는것이가장큰문제로생각된다. 항생제의측면에서만본다면용량을늘리거나기간을연장하거나아니면내성이없는약제를첨가하여사용하는방법이원칙인데, 이를고려한새로운제균요법의수립이가장필요한상황이다. H. pylori 제균치료효과를극대화하기위해개인의유전적다형성, 항생제내성, 연령등다양한인구학적요소들을고려한개별화맞춤형치료의시대가도래하고있다. 항생제감수성검사가가능하다면이결과에맞추어적절한항생제를병합처방하는것이기본개념인데, 실제임상에서항생제감수성검사를시행하기어려운경우가많으므로최근에는이를손쉽게알수있는다양한상품개발에노력을기울이고있다. 이밖에도흡연은제균의효과를감소시킬수있음을, 96 그리고동반된만성질환 ( 당뇨, 97 고혈압, 98 만성신부전 99 등 ) 또한제균율에영향을줄수있음을고려해야하겠다. 고령환자의경우제균치료시부작용의발생빈도가높으며일부에서는연령이증가할수록제균율이감소한다는보고도있다. 25 하지만이러한인구학적요소들에대한확실한증거는부족한실정이어서추가적인연구가필요하겠다. 1) CYP2C19 유전자다형성적절한위산억제와 H. pylori 균주내성여부가제균성공에중요한요인이되기때문에 PPI를기본으로하는표준삼제요법에서 CYP2C19 유전자형은제균성공을판가름하는중요한인자가될수있다. PPI는간에존재하는 cytochrome p450 system 중주로 CYP2C19에의해대사되는것으로알려져있다. CYP2C19은유전자형의다형성에따라신속대사자 (extensive metabolizer), 중간대사자 (intermediate metabolizer), 그리고대사저하자 (poor metabolizer) 로분류할수있다. 대사저하자의경우 PPI의대사가매우천천히일어나기때문에신속대사자에비해생체이용률이 20배가량높은것으로알려져있다. 100 CYP2C19의유전자형은동서양에서확연한차이를보이는데, 대사저하자는코카시안이나아프리카아메리칸에서는 3-4% 에불과한반면한국인, 중국인에서는 14% 를, 일본인에서는 22.3% 를차지한다. 100,101 CYP2C19 유전자형에대한이전 3개의메타분석에따르면 omeprazole 은 CYP2C19 유전자형에영향을받는반면, rabeprazole은영향을받지않았다 최근에무작위배정연구들을기반으로한메타분석에서는대사저하자가신속대사자에비해제균율이높았고 omeprazole과 lansoprazole을투여하였을경우제균율은 CYP2C19 유전자형의영향을받았으나 rabeprazole과 esomeprazole은 CYP2C19 유전자형에영향을받지않는것으로보고되었다. 105 국내에서는 lansoprazole과 rebeprazole을이용한삼제요법의제균율은 CYP2C19 유전자형에영향을받지않았으나, 106 다른연구에서는 pantoprazole과 esomeprazole 포함삼제요법에서대사저하자의제균율이신속대사자보다의미있게높았다. 6,107 그러나아직까지국내에서 CYP2C19의유전자형을임상에서검사하기는 Vol. 63 No. 3, March 2014

9 166 이주엽, 김나영. 헬리코박터제균치료의미래 쉽지않다. 이러한이유로 Second Asia-Pacific Consensus Guideline에서는 PPI의종류와용량을조절하는것이더실질적인접근방법이라고제시하고있다. 51 2) PCR을이용한 clarithromycin 내성돌연변이검사여러연구를통하여 clarithromycin 감수성 H. pylori 감염환자의경우 clarithromycin 포함삼제요법의성공률이 90-95% 를상회한다는사실이알려져있다 따라서우리나라와같이 clarithromycin 내성률이높은지역의경우치료전내성검사를통한제균치료처방이가장효과적인방법이라하겠다. 하지만기존의내성검사방법인 H. pylori 배양및최소억제농도 (minimum inhibitory concentration) 검사는다른세균에비해매우까다롭고시간이수주에이를정도로오래걸리며표준화또한되어있지않아, 시행을하기위해서는많은노력과비용이소요되므로실제임상에서거의시행되지못하고있는실정이다. 최근기존의방법을대체할수있는신속내성검사에대한연구가지속적으로이루어지고있는데, 그중하나로 dual priming oligonucleotide (DPO)- based multiplex PCR검사를도입하여개발된 Seeplex ClaR- H. pylori PCR kit (Seegene Inc., Seoul, Korea) 가있다. 111 이방법은 clarithromycin 23S rrna 점돌연변이중내성여부와관련성이많이알려진 A2142G, A2143G 돌연변이여부를중합효소연쇄반응 (PCR) 을이용해서측정하는것인데, 112 최근상품화되어사용되고있다. 이검사는위점막조직만으로도비교적간단히검사가가능하고검사소요시간은수시간에불과하다는장점이있으며, 민감도와특이도는 80-85% 정도이다. 110 비용은신속요소분해검사 (rapid urease test) 와비슷하고신기술로보험적용을고려하고있어, 향후일차의료기관에서도수탁검사를이용하면사용할수있을것으로생각된다. 113 DPO-based multiplex PCR 방법을통해 23S rrna의점돌연변이를판별하여치료한군과경험적치료로 PPI, amoxicillin, clarithromycin을사용한군, 그리고 PPI, amoxicillin, metronidazole을사용한군의총 3군으로나누어서맞춤형치료의효과를분석한국내연구에서는맞춤형치료의제균율이 91.2% 로다른두군의 75.9%, 79.1% 보다유의하게높은결과를보였다. 114 일본의한연구에서도제균치료전대상환자들의 CYP2C19 유전자형과 H. pylori 23S rrna genotype 분석을통하여 clarithromycin 내성여부를조사하고이에맞추어 PPI 용량및투여간격과 clarithromycin 사용여부를결정하는맞춤형치료를시행하였고, 95% 이상의제균성공으로표준삼제요법에비해우수한성적을보여준바있다. 115 앞으로이러한신기술을이용한맞춤형치료는제균치료효과극대화에많은도움을줄것으로생각되며, 맞춤형치료 가표준 1차제균치료로인정받기위해서는제균율및비용효과의우수성에대한더많은연구가뒷받침되어야할것이다. 결 론 H. pylori에감염된모든환자를제균치료대상으로하겠다는최근의변화들은아직까지 H. pylori 감염률이 50% 이상으로높고위암의유병률이높은우리나라에서매우주목해야할사항이다. Clarithromycin 내성이높은한국에서표준삼제요법을 1차치료로사용하는것에대해서는재고가필요하며, 순차치료는표준삼제요법보다는효과가우월하지만이또한만족할만한효과를보이지않고있어서새로운제균요법의수립이절실한상황이다. 이러한요법이수립되기전에는 23S rrna의점돌연변이를판별하여제균치료요법을선택하는방안으로제균치료효과를극대화시키는것이필요할것으로보인다. 향후효과적치료법의수립을위해서는전국적인 H. pylori 내성조사및여러가지새로운제균요법에대한많은연구들이필요하겠다. REFERENCES 1. McColl KE. Clinical practice. Helicobacter pylori infection. N Engl J Med 2010;362: NIH Consensus Conference. H. pylori in peptic ulcer disease. NIH Consensus development panel on Helicobacter pylori in peptic ulcer disease. JAMA 1994;272: Graham DY, Lew GM, Klein PD, et al. Effect of treatment of Helicobacter pylori infection on the long-term recurrence of gastric or duodenal ulcer. A randomized, controlled study. Ann Intern Med 1992;116: Bayerdörffer E, Neubauer A, Rudolph B, et al. Regression of primary gastric lymphoma of mucosa-associated lymphoid tissue type after cure of Helicobacter pylori infection. MALT Lymphoma Study Group. Lancet 1995;345: 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: Lee JY, Kim N, Kim MS, et al. Factors affecting first-line triple therapy of Helicobacter pylori including CYP2C19 genotype and antibiotic resistance. Dig Dis Sci doi: / s World Gastroenterology Organisation global guideline: Helicobacter pylori in developing countries. J Dig Dis 2011;12: Klein PD, Graham DY, Gaillour A, Opekun AR, Smith EO. Water source as risk factor for Helicobacter pylori infection in Peruvian children. Gastrointestinal Physiology Working Group. Lancet 1991;337: The Korean Journal of Gastroenterology

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