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1 Korean J Gastroenterol Vol. 58 No. 2, REVIEW ARTICLE 국내 Helicobacter pylori 의제균치료 김승영, 정성우 고려대학교의과대학내과학교실 Helicobacter pylori Eradication Therapy in Korea Seung Young Kim and Sung Woo Jung Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea Helicobacter pylori (H. pylori) is known to be associated with many gastrointestinal diseases including peptic ulcer. In Korea, eradication of H. pylori is recommended for peptic ulcer disease, low grade gastric mucosa-associated lymphoid tissue lymphoma, and early gastric cancer. Standard triple therapy using proton pump inhibitor, clarithromycin, and amoxicillin and bismuth-containing quadruple therapy have been the main first-line and second-line therapy for H. pylori in Korea. Although eradication rate of second-line quadruple therapy remains similar to that of the past, the success rate of eradication with triple therapy has decreased with increasing antimicrobial resistance to H. pylori. There is no standard third-line therapy, and some regimens that incorporate levofloxacin, moxifloxacin, and rifabutin can be used. New regimens such as sequential or concomitant therapy are suggested as alternative treatment for H. pylori. We need more well designed randomized controlled studies to choose proper treatment for H. pylori infection. (Korean J Gastroenterol 2011;58:67-73) Key Words: Helicobacter pylori; Drug therapy; Combination 서론 Helicobacter pylori (H. pylori) 는전세계인구의약 50% 감염률을보이는가장흔한인체감염균중의하나로, 상부위장관질환의중요한원인중하나로알려져있다. 현재까지 H. pylori는소화성궤양, 위암및변연부 B세포림프종발생에있어중요한원인인자로밝혀졌고, 기능성소화불량증, 위의과형성용종, 철결핍성빈혈등기타질환과의연관성들이제시되고있다. 1 H. pylori와위장관질환의연관성이밝혀지면서, 국내에서도 1998년대한 Helicobacter 및상부위장관연구학회에서 H. pylori 치료에대한합의가발표되었고, 지난 10여년간제균치료가활발하게이루어져왔다. 제균치료는 H. pylori 관련소화성궤양의재발을줄이는데크게기여하였으며, 위의변연부 B세포림프종관해에도중요한역할을하 고있다. 2-4 그러나최근 H. pylori의항생제내성의증가로인해일차치료의성공률이점차감소하고있어이에대한검토와새로운제균치료정립의필요성이대두되고있다. 이글에서는국내 H. pylori 제균치료의현황을살펴보고, 제균율감소와함께연구되고있는여러제균치료법들을정리해보고자한다. 본론 1. 제균의적응증국내 H. pylori 유병률은 1998년 66.8% 에서 2005년 59.6% 로감소하고있으나, H. pylori 항체에대한혈청학적유병률은약 50% 로국민의반수가감염되어있고특히, 16세이상의성인에서는약 2/3가감염되어있다. 5 각국의지침에서는 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 : 정성우, , 경기도안산시단원구고잔 1동 516, 고려대학교의과대학안산병원내과학교실 Correspondence to: Sung Woo Jung, Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, 516, Gojan-dong, Danwon-gu, Ansan , Korea. Tel: , Fax: , sungwoojung@korea.ac.kr Financial support: None. Conflict of interest: None. Korean J Gastroenterol, Vol. 58 No. 2, August

2 68 김승영, 정성우. 국내 Helicobacter pylori 의제균치료 Table 1. Indication for Helicobacter pylori Eradication Definite indication 1) Peptic ulcer including scar 2) Marginal Zone B cell lymphoma (MALT type) a 3) Early gastric cancer Recommended indication 1) First relatives of gastric cancer patients 2) Unexplained iron deficiency anemia 3) Chronic idiopathic thrombocytopenic purpura Possible indication 1) Atrophic gastritis 2) Non-ulcer dyspepsia 3) Long-term use of NSAID MALT, mucosa-associated lymphoid tissue. a Low grade MALToma has been renamed as Marginal zone B cell lymphoma (MALT type). 모든소화성궤양환자에서 H. pylori의제균치료를권고하고있으며, 위의변연부 B세포림프종, 조기위암의내시경절제후, 위암의가족력이있는경우및만성위축성위염등이제균치료의대상이되고있다. 6-8 국내에서는 1998년대한 Helicobacter 및상부위장관연구학회에서 한국인에서의헬리코박터파일로리의진단과치료 에대한합의도출이후 2009년대한상부위장관ㆍ헬리코박터학회에서국내외에서발표된다양한문헌들을검토하여치료에대한적응증을제시하였다 (Table 1). 새로운가이드라인에서는 H. pylori 제균대상으로, 반흔을포함한소화성궤양및변연부 B세포림프종과함께조기위암환자를추가하였고, 위암직계가족, 설명되지않는철분결핍빈혈, 만성특발혈소판감소증에서제균치료를추천하였다 표준제균치료 1) 일차치료최근전세계적으로 clarithromycin을포함하는삼제요법의제균율이감소하고있음에도불구하고, 10,11 프로톤펌프억제제 (proton pump inhibitor, PPI) 와 amoxicillin, clarithromycin을사용하는삼제요법은최근까지대부분의국가에서표준치료로사용하고있다. 2009년대한상부위장관ㆍ헬리코박터학회에서발표된가이드라인에서도 PPI (standard dose bid) 와 clarithromycin (0.5 g bid), amoxicillin (1 g bid) 을이용한삼제요법의 1주내지 2주투여를표준일차치료법으로권고하고있다. 표준삼제요법의제균율은 1998년까지는 90% 이상을보여매우효과적인것으로인정받았으나, 그이후점차성공률이감소하여 75% 까지보고된바있다. 12,13 국내단일기관에서 5년이상의기간동안제균율의변화를본연구들을보면 6개연구중세연구에서통계적으로의미있는감소추세를보였다 (Fig. 1). 11,14-18 Fig. 1. The change of per protocol eradication rates of standard triple therapy in Korea. 11,14-18 Studies maked with * showed significant decreasing trend of eradication rate. 제균율이감소하는가장큰원인은항생제내성률의증가이다. 국내한연구에서 clarithromycin 내성률은 1994년에 2.8% 에서, 2003년 13.8% 로급격히증가하였으며, 다른연구에서도 2005년이전의경우 16.7% 에서 2007년부터 2009년까지는 38.5% 로내성률증가를보고하였다. 19,20 치료기간에따른삼제요법의제균율을살펴보면, 2007년다기관전향연구에서 7일에서 14일로의기간연장이의미있는제균율상승을보여주지못하였으나, 년국내연구를대상으로한메타분석에서는 7일에서 14일로의기간연장이약 10% 정도의제균율상승을보였다. 22 PPI 종류에따른제균율은몇몇연구들에서 CYP219 유전자다형성에영향을덜받는 rabeprazole이나 esomeprazole이다른약제에비해비교적더좋은제균율을보였으나임상적으로고려할만한차이를보인연구는드물었다. 23,24 또한, PPI의특허약 (original) 과복제약 (generic) 에따른제균율차이에대하여 pantoprazole을대상으로분석한연구에서특허약과복제약에따른제균율의차이는없었다. 25 표준삼제요법에서 amoxicillin의약리학적특성을고려하여동일용량의 amoxicillin을하루두번과네번으로나누어투여하여제균율을비교한연구에서도제균율의차이는보이지않았다. 26 표준삼제요법에 probiotics를추가하였을때더나은제균율을보인연구들이있으나아직더많은추가연구가필요한실정이다. 27,28 2) 이차치료 대한상부위장관ㆍ헬리코박터학회에서발표된가이드라인에서는이차치료제로 PPI (standard dose bid) 와 metronidazol (0.5 g tid), bismuth (120 mg qid), tetracycline (0.5 g qid) 의사제요법을 1주내지 2주투여할것을권고하고있다. Bismuth를포함하는사제요법은복용방법이복잡하고 The Korean Journal of Gastroenterology

3 Kim SY and Jung SW. Helicobacter pylori Eradication Therapy in Korea 69 결핵치료제로사용되는 rifabutin에대한내성획득우려가있어사용에제한이있겠다. 흥미롭게도한연구에서 bismuth 포함사제요법의이차치료에실패한 40명의환자들에게다시한번같은치료법을사용하였을때, 75% 의제균율을보여 35 삼차치료를시도하기전이차사제요법으로재치료하는것을고려해볼수있겠다. 3. 새로운제균치료법 Fig. 2. The change of per protocol eradication rates of second-line bismuth-containing quadruple therapy in Korea. 11,16,18,30 There was no decreasing trend in eradication rates. 부작용발생률이 30% 이상높으나전세계적으로가장많이사용되고있다. 국내사제요법의제균율은 7일투여시 63-81% 로보고되며, 현재까지제균율의감소추세는뚜렷하지않다 (Fig. 2). 11,16,18,29,30 치료기간을 7일에서 14일로연장하였을때, 제균율은 69-96% 로보고되며, 최근연구에서는 1 주투여보다 2주투여의제균율이의미있게높아향후투여기간에대한논의가다시필요할것으로생각된다. 31 3) 삼차치료 H. pylori의이차제균치료에실패하였을경우, 삼차치료에대해서는아직표준화된치료법이없다. 지금까지연구들에서는 levofloxacin이나 moxifloxacin, rifabutin을이용한방법들이보고되었다. Levofloxacin을이용한치료법으로 PPI (standard dose bid) 와 levofloxacin ( mg bid), amoxicillin (1 g bid) 을 7일또는 10일투여할경우국내에서는 % 정도의제균율을보이고있다. 32,33 이는국외제균성적에비해낮은것으로, 국내에서 floroquinolone계항생제사용증가에따른내성률증가가원인으로생각된다. 같은 floroquinolone 제제인 moxifloxacin은이차치료법으로 esomeprazole, amoxicillin과같이 10일간사용하였을때, 71.9% 의제균율을보였다. 34 그러나호흡기질환및이비인후과질환에서국내 moxifloxacin 사용이증가하고있으며, 내성획득이빠르기때문에시간이지남에따라치료성공률이감소할것으로생각한다. Rifabutin은국내에서삼차치료로사용한연구는없지만, PPI, amoxicillin과사용하였을때 % 의제균율을보여하나의대안으로사용될수있을것으로기대된다. 그러나우리나라는결핵유병률이높아비정형결핵이나다약제내성 표준삼제요법의제균율이감소하면서여러치료방법들이경험적일차치료의대안으로제시되고있다. 1) Sequential therapy 순차적인 10일치료는 PPI와 amoxicillin 2제를 5일간투여후 PPI와 clarithromycin, 그리고 tinidazole이나 metronidazole 3제를 5일간순차적으로투여하는방법이다. 순차적인치료의이론적근거는초기 amoxicillin을사용하는이제요법으로위내의 H. pylori균수를감소시켜이후투여하는삼제요법의효과를높이고, amoxicillin이세포벽을약화시킴으로써 clarithromycin 내성발현을줄인다는것이다. 36,37 외국의메타분석에서는표준삼제요법과비교하였을때우수한제균성적을보였으나, 10,38,39 국내에서최근발표된연구에서는두치료법의제균율이의미있는차이가없거나오히려삼제요법에못미치는결과를보여기간및용량의변화나추가적인연구가필요할것으로생각된다. 40,41 2) Concomitant therapy Bismuth를사용하지않는사제요법으로순차치료에사용되는세가지항생제, amoxicillin, clarithromycin, metronidazole 또는 tinidazole을 PPI와함께동시에투여하는방법이다. 최근메타분석에서제균율은 90% (intention to treat) 정도로삼제요법에비해우수한결과를보였으나메타분석에포함된대부분의연구들이 2000년대초반까지의연구였다. 42,43 이에저자들은소화성궤양환자들을대상으로 concomitant 5일치료의제균효과를분석하였다. 44 제균율은 intention-to treat 분석에서 80.7%, per protocol 분석으로 91.4% 로우수한제균율을보였다. 그러나경미하지만부작용발생이 27-51% 로비교적높았고, 사제요법을일차치료로사용하였을때 H. pylori의내성획득에대하여아직연구된바가없어이차치료로사용할수있는약제의선택에어려움이있을수있다는제한이있다. 3) Dual therapy ( 이제요법 ) PPI와 amoxicillin만을사용하는이제요법은치료성공에중요한위내산도를적절히억제하여내성발생이적은 amoxicillin의제균효과를높이려는의도에서출발한치료이다. H. pylori의제균에있어서위산도를 ph 4 이상으로유지하는것이항생제효과를증가시키며, PPI를고용량으로또, Vol. 58 No. 2, August 2011

4 70 김승영, 정성우. 국내 Helicobacter pylori 의제균치료 같은용랑이라도자주투여하는것이위산억제에더효과적임이증명되었다 특히 CYP21C9 유전자다형성에서 extensive metabolizer가많은아시아에서는 PPI를하루여러번투여하여위산을억제하는것이중요하다. 이제요법에대한국내연구는 2000년대초반까지의연구가대부분이며, 삼제요법과동일한용량의 amoxicillin을 PPI와같이사용하여 % 정도의만족스럽지못한제균율을보였다 그러나약리학적특성을고려하여 PPI 및 amoxicillin을더자주투여하고, PPI 용량을늘려투여하였을경우이제요법은 % 의높은제균율을보였다 최근국내의연구에서 2009년부터 2010년까지 lansoprazole 30 mg tid와 amoxicillin 750 mg tid를 14일간투여하는이제요법의제균율은 78.4% (per protocol) 로같은기간삼제요법의제균율 82.8% 와비슷한성공률을보였다. 55 제균율면에서일차치료로사용하기에는무리가있으나, PPI (standard dose) 와 amoxicillin (500 mg) 을하루네번투여하는고용량이제요법은구제요법의하나로제시되고있다. 56 4) Tailored therapy ( 맞춤개별화치료 ) H. pylori 제균성공에는적절한위산억제와 H. pylori 균주의내성여부가중요하기때문에 PPI를기본으로하는표준삼제요법에서 CYP2C19 유전자형은제균성공을판가름하는중요한인자가될수있다. 57,58 국내에서는 lansoprazole과 rabeprazole을이용한삼제요법의제균율은 CYP2C19 유전자형에영향을받지않았으나, 다른연구에서는 pantoprazole과 esomeprazole 포함삼제요법에서 extensive metabolizer 환자의제균율이 poor metabolizer 환자의제균율보다의미있게떨어져있는결과를보였다. 59,60 일본의한연구에서는 H. pylori를치료하기전대상환자들의 CYP2C19형과 H. pylori 23S rrna genotype 분석을통하여 clartirhomycin 내성여부를조사하고, 이에맞추어 PPI의투여간격과 clarithromycin 사용여부를결정하는맞춤형치료를제안하였고, 95% 이상의제균성공으로표준삼제요법에비해우수한성적을보여준바있다. 61 그러나아직까지국내에서 CYP2C19형이나 clarithromycin 내성을임상에서검사하기는쉽지않아적용하기는어렵다. 4. 효과적인제균치료 H. pylori는생체외에서는많은항생제에감수성을가지고있으나, 임상에서의제균치료는어려움이있을수있다. 그이유들로는 metronidazole이나 clarithromycin 같은항생제에대한내성이발현될수있고, 위안의 H. pylori 수가많기때문에발생하는표준접종량효과 (inoculum effect) 가나타날수있으며, 위내의높은산성환경과 H. pylori가위점막겔층에존재하여항생제침투가어려운환경적인요인등이 있을수있다 또한제균실패는낮은순응도, 흡연등의환경적요인과항생제내성 H. pylori 균주, caga( ) 나 vaga s2형같은균주의병원인자 (virulence factor), PPI의용량이나투여간격과관련되는불충분한위산억제등의여러요인과관련되어있다. 65 Clartithromycin 내성이발생하였을때, clarithromycin을포함하는제균요법의성공률은 70% 정도감소하며, nitroimidazole내성은삼제나사제요법의효과를 50% 정도로감소시킨다. 66,67 항생제내성으로인한제균실패를줄이는가장좋은방법은치료전에 H. pylori 균주의항생제내성검사를실시하는것이지만, 현재로서임상에서 clarithromycin 내성검사를접하기쉽지않으며, 가격대비효과적이지않다. 따라서, amoxicillin이나 tetracycline, bismuth 같이내성이거의생기지않는항생제들이중요한구성약제가될수있으며, 지역에맞는효과적인제균치료법을찾기위해서는그지역의 H. pylori의항생제내성률을알고, 가장효과적인항생제조합을선택해야한다. 위산이충분히억제되지않으면, clarithromycin이나 amoxicillin같은항생제가불안정해져제균효과가감소하기때문에산도조절은 H. pylori 제균에중요한요소이다. 47 위산억제에중요한 PPI는그종류에따라경구생체이용률이나표준용량이다르므로, H. pylori를제거하기위한보다적당한산도를유지하기위해서는각약제의특성을고려하여투여간격및용량을결정해야한다 년발표된연구에서는 H. pylori 제균실패를줄이기위한몇가지규칙을제시하기도하였는데 69 1) PPI/amoxicillin/clarithromycin 조합의표준삼제요법은 per protocol (PP) 로 90% 이상의제균성공을보이는지역에서만사용할것, 2) 약제는저용량으로효과가증명되지않았다면고용량으로사용할것, 3) 짧은기간으로효과가증명되지않았다면 14일간치료할것, 4) clarithromycin을상용처방하는지역에서는 clarithromycin 포함삼제요법은사용하지말것, 5) fluoroquinolone이여타의감염질환에사용이된다면제균치료에서사용하지말것, 6) 제균실패이후에는내성이있을것으로예상되는약제 ( 즉, clarithromycin이나 fluoroquinolone) 는사용하지말아야한다는것이다. H. pylori 제균치료법으로적합하기위해서는 PP 분석에서 90% 이상, intention to treat 분석에서 80% 이상의치료성공률을보여야하며심각한부작용발생률이 5% 이하여야한다. 9 또한 H. pylori는치료에실패한경우사용된약제에대한내성발현율이높아치료후내성균발현율이 30% 이하인약제조합이바람직하다. 국내 clarithromycin 내성률이나최근일차치료의성적을고려하였을때, 표준삼제요법을효과적인일차치료법으로 The Korean Journal of Gastroenterology

5 Kim SY and Jung SW. Helicobacter pylori Eradication Therapy in Korea 71 생각하기는어렵다. 그러나현재까지의국내의연구들만으로는표준삼제요법보다우월한효과를보이면서치료실패시이차및삼차치료의다음항생제선택까지용이한치료법을정하는데는어려움이있는실정이다. 결 론 H. pylori 제균에있어일차치료는삼제요법이사용되고있으며, 최근항생제내성의증가와함께제균율은점차감소하고있어 80% 정도로보고하고있다. 일차치료실패시에사용하는이차치료로는 bismuth를포함하는사제요법이사용되고있으며이차치료의제균성공률은아직까지는크게감소하지않고있다. 현재표준으로사용하는삼제요법은그효과가급격히떨어짐에따라일차치료로다른치료법을고려해야할시점이다가오고있으며, 여러가지새로운치료법들이제시되고있다. 새로운일차치료법이나이차치료에실패하였을때구제요법에대하여국내연구들이부족한실정이며명확한가이드라인이없는실정이다. 이를위해 H. pylori의항생제내성조사및이를바탕으로하는여러새로운제균요법에대한대규모전향연구들이필요하다고생각한다. REFERENCES 1. Suerbaum S, Michetti P. Helicobacter pylori infection. N Engl J Med 2002;347: Korean H. pylori Study Group. Diagnosis and treatment of Helicobacter pylori infection in Korea. Korean J Gastroenterol 1998;32: 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: Yim JY, Kim N, Choi SH, et al. Seroprevalence of Helicobacter pylori in South Korea. Helicobacter 2007;12: Asaka M, Kato M, Takahashi S, et al. Guidelines for the management of Helicobacter pylori infection in Japan: 2009 revised edition. Helicobacter 2010;15: Chey WD, Wong BC; Practice Parameters Committee of the American College of Gastroenterology. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol 2007;102: Malfertheiner P, Megraud F, O'Morain C, et al. Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus Report. Gut 2007;56: Kim N, Kim JJ, Choe YH, Kim HS, Kim JI, Chung IS. Diagnosis and treatment guidelines for Helicobacter pylori infection in Korea. Korean J Gastroenterol 2009;54: Jafri NS, Hornung CA, Howden CW. Meta-analysis: sequential therapy appears superior to standard therapy for Helicobacter pylori infection in patients naive to treatment. Ann Intern Med 2008;148: Song JG, Lee SW, Park JY, et al. Trend in the eradication rates of Helicobacter pylori infection in the last 11 years. Korean J Med 2009;76: Lee JY, Kim W, Gwak GY, et al. Reinfection rate and clinical manifestation of Helicobacter pylori-positive peptic ulcer disease after triple therapy containing clarithromycin. Korean J Gastroenterol 2002;39: Kim BW, Choi MG, Choi H, et al. Pooled analysis of antibiotic therapy for Helicobacter pylori eradication in Korea. Korean J Gastroenterol 1999;34: Cho DK, Park SY, Kee WJ, et al. The trend of eradication rate of Helicobacter pylori infection and clinical factors that affect the eradication of first-line therapy. Korean J Gastroenterol 2010; 55: Choi YS, Cheon JH, Lee JY, et al. The trend of eradication rates of first-line triple therapy for Helicobacter pylori infection: single center experience for recent eight years. Korean J Gastroenterol 2006;48: Chung JW, Lee GH, Han JH, et al. The trends of one-week first-line and second-line eradication therapy for Helicobacter pylori infection in Korea. Hepatogastroenterology 2011;58: Chung WC, Lee KM, Paik CN, et al. Inter-departmental differences in the eradication therapy for Helicobacter pylori infection: a single center study. Korean J Gastroenterol 2009;53: Na HS, Hong SJ, Yoon HJ, et al. Eradication rate of first-line and second-line therapy for Helicobacter pylori infection, and reinfection rate after successful eradication. Korean J Gastroenterol 2007;50: Hwang TJ, Kim N, Kim HB, et al. Change in antibiotic resistance of Helicobacter pylori strains and the effect of A2143G point mutation of 23S rrna on the eradication of H. pylori in a single center of Korea. J Clin Gastroenterol 2010;44: Kim JM, Kim JS, Jung HC, Kim N, Kim YJ, Song IS. Distribution of antibiotic MICs for Helicobacter pylori strains over a 16-year period in patients from Seoul, South Korea. Antimicrob Agents Chemother 2004;48: Kim BG, Lee DH, Ye BD, et al. Comparison of 7-day and 14-day proton pump inhibitor-containing triple therapy for Helicobacter pylori eradication: neither treatment duration provides acceptable eradication rate in Korea. Helicobacter 2007;12: Jung HS, Shim KN, Park H, et al. Meat-analysis of the H. pylori eradication rates according to the duration of the first-line therapy. Korean J Helicobacter Upper Gastrointest Res 2008; 8: Gisbert JP, Khorrami S, Calvet X, Pajares JM. Systematic review: Rabeprazole-based therapies in Helicobacter pylori eradication. Aliment Pharmacol Ther 2003;17: Laine L. Review article: esomeprazole in the treatment of Helicobacter pylori. Aliment Pharmacol Ther 2002;16(Suppl 4): Vol. 58 No. 2, August 2011

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