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1 REVIEW ISSN , The Korean Journal of Helicobacter and Upper Gastrointestinal Research, 2012;12(4): 헬리코박터제균치료의현재와미래 - 제균치료의미래 송현주 제주대학교의학전문대학원내과학교실 Future of Helicobacter pylori Eradication-New Trials Hyun Joo Song Department of Internal Medicine, Jeju National University School of Medicine, Jeju, Korea The efficacy of standard 7 14 day triple therapy is decreasing, mainly due to increased primary bacterial resistance to antibiotics. Recent published studies have therefore focused on developing alternative strategies for first-line eradication of Helicobacter pylori. Clear evidence now exists that levofloxacin is a viable option for first-line therapy. In addition, data have emerged that the probiotic Saccharomyces boulardii and Lactobacillus supplementation may be a useful adjunct to antibiotic therapy. Among the novel molecules, benzimidazole-derivatives, polycyclic compounds, pyloricidin, and arylthiazole analogues seem to be the most promising. The sequential and concomitant regimes have also been studied in new settings and may have a role in future algorithms. Other studies promote individualized therapies based on host polymorphisms, age, and other demographic factors and resistance. In the near future, tailored therapy could optimize eradication regimens within the different countries. This article reviews the literature published pertaining to new clinical trials of H. pylori eradication. (Korean J Helicobacter Up Gastrointest Res 2012;12: ) Key Words: Helicobacter pylori; Clinical trial 서 Helicobacter pylori ( 이하헬리코박터 ) 의감염이점점감소함에도불구하고, 헬리코박터의감염은전세계적으로퍼져있다. 1 현재까지양성자펌프억제제 (proton pump inhibitor, PPI) 를근간으로하는항생제조합치료가주를이루고있으나, 모든환자에서헬리코박터를제균할수있는치료는없으며, 새로운약제와치료적인접근이필요하다. 치료실패의원인들로는항생제내성의증가뿐만아니라, CYP2C19 의유전자다형성, 체질량지수의증가, 흡연, 낮은약제순응도, 재감염등이있다 년도대한상부위장관ㆍ헬리코박터학회지에따르면현재국내헬리코박터치료에대한 1차치료가이드라인은 PPI 를근간으로 clarithromycin 과 amoxicilline 3제요법을 1 2 주사용하고, 치료에반응하지않은경우는 4제요법 (PPI+metronidazole+tetracycline+bismuth) 을권고하고있다. 3 2차제균치료의성공률은과거와비슷하나, 성공적인제균율은항 Received: October 16, 2012 Accepted: November 9, 2012 Corresponding author: Hyun Joo Song Department of Internal Medicine, Jeju National University Hospital, 15 Aran 13-gil, Jeju , Korea Tel: , Fax: , songhj@jejunu.ac.kr 생제내성이증가하면서감소하고있다. 4 Maastricht 가이드라인에따르면일차제균치료에서수용할만한최소한의 intention-to-treat (ITT) 제균율은 80% 로보고있다. 5 최근에많은연구에서새로운치료적목표로헬리코박터제균에대한시도들은지속되고있다. 본고에서는최근에시도되고있는새로운헬리코박터제균치료제및치료방법에대한문헌들을위주로정리하여보고자한다. 1. Levofloxacin 본 Levofloxacin 을일차치료로많은사용한시도들이있었다. 6 Levofloxacin 은표준일차치료또는순차적제균요법 (sequential therapy) 에 clarithromycin의대체로사용될수있다. Levofloxacin 병합요법에대한대규모연구에서 perprotocol (PP) 분석에서 omeprazole-clarithromycin-amoxicillin 의삼제요법에서 66% 를 omeprazole-levofloxacin-amoxicillin에서 83%, omeprazole-amoxicillin-levofloxacin-metronidazole 에서 85% 로순응도와이상반응에서는차이가없었다. 7 따라서 clarithromycin 내성이 15% 가넘는경우는순차적인 levofloxacin 치료가도움이될수있고, 또다른연구에서 levofloxacin 순차요법의헬리코박터제균율이 96% 로, clari- Copyright 2012 Korean College of Helicobacter and Upper Gastrointestinal Research The Korean Journal of Helicobacter and Upper Gastrointestinal Research is an Open-Access Journal. All articles are distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 Hyun Joo Song: Future of Helicobacter pylori Eradication-New Trials thromycin 순차요법 81% 보다우월함을보이고있다. 8 중국에서 300명의환자를표준 clarithromycin 3제요법과 levofloxacin 3제요법을비교한연구에서 PP 분석에따르면각각제균율이 78%, 83% 로통계적인차이는없었으나, levofloxacin 3제요법이일차치료로대안이될수있음을보여주었다. 9 Levofloxacin 3제요법과표준 clarithromycin 3제요법을비교했을때제균율은 69.4%, 74.0% 였고 (P =0.52), levofloxacin 3제요법과표준 2차치료와비교연구에서도제균율은각각 62.5%, 40.0% 였다 (P =0.34). 10 그러나, levofloxacin 내성이문제가될수있는데, Kim 11 의보고에의하면 levofloxacin의항생제내성률은 1987년과 1994년에는전혀관찰되지않았으나, 2003년분리균주에서는 21.5% 를나타냈다. 또한 1차제균시행전 2004년과 2007년의 floroquinolone 내성률은 15.6% (29/185) 로높게관찰되었다. 국내에서 2008년도 levofloxacin 내성이 23.2% 이며, 12 levofloxacin 에의한 2차치료가 bismuth 를근거로한약제와 PP 분석에서각각 53.3%, 62.9% 로비슷한치료효과를보였다 유산균제제 유산균제제는헬리코박터제균치료에유용하게사용될수있으며환자의순응도를증가시키고, 부작용을감소시킨다. 6 특히 Saccharomyces boulardii 가보조제로서효과가입증되었는데, 국내연구에서 1주일간의 1차표준치료와함께 4주간투약한군과투약받지않은경우제균율 ITT 분석에서각각 80.0%, 71.6%, PP 분석에서도 85.4%, 80.0% 로의미있는차이를보였다. 14 1,307명을대상으로한 5개의무작위배정연구의메타분석에서도 S. boulardii 가제균율을의미있게증가시키고 (relative risk [RR], 1.13; 95% CI, ), 부작용을감소시키며 (RR, 0.46; 95% CI, ), 특히설사를감소시켰다 (RR, 0.47; 95% CI, ). 15 다른유산균제제들의경우 Lactobacillus acidophilus에대한연구에서는 1차표준치료에 L. acidophilus 추가가제균율의차이가없다는보고도있었으나, 16 1,107명을대상으로 11 개의무작위대조연구의국내메타분석연구에서 Lactobacillus 보조치료가위약군또는보조치료를하지않은군에비해제균율을의미있게증가시켰다 (84.7% vs. 78.8%; OR, 1.75; 95% CI, ). 17 또한약물부작용을의미있게감소시켰는데 (35.4% vs. 48.6%, OR, 0.56; 95% CI, ), 특히설사 (7.5% vs. 20.6%; OR, 0.31; 95% CI, ), 가스참 (19.2% vs. 29.9%; OR, 0.53; 95% CI, ), 입맛변화 (17.6% vs. 34.8%; OR, 0.37; 95% CI, ) 등에효과가있었다. Bifidobacterium 을포함한요거트를 1차표준치료와같이치료한군에서 1차표준치료단독에비해헬리코박터의제균율은약간높았으나통계적인차이는보이지않았고 (66% vs. 53%; P =0.350), 구내염이나변비의횟수는의미있게감소시켰다. 18 따라서, 헬리코박터제균시유산균제제의보조치료가표준치료로사용될가능성이있다. 3. 새로운분자들 지난 10년간새로운항생제특허가헬리코박터균에영향이있다고주장되어왔다. 19 흥미로운것은새로운분자들 (molecules) 이체외에서 clarithromycin 과 metronidazole 에내성이있는헬리코박터에매우높은살균효과 (bactericidal effect) 를가진다는것이다. 또한어떤분자들은낮은 ph에서도살균력을가지며, 헬리코박터치료에확실한효과가있다. 특히다른 benzimidazole-derivatives와 polycyclic compounds 가특허를받았고, 헬리코박터에효과적이다. 20 Pyloricidin A, B, C-자연항생제계열이매우강력하며세균의최소억제농도 (minimum inhibitory concentration, MIC 90) 가 mg/dl 로선택적인살균효과를가진다. 20 또한 arylthizole analogues 에서 thienylthiazole derivative 44는 MIC 90 이 mg/dl 로매우강력하다. 특히일부 isothiazole derivatives 는헬리코박터치료시, 생체내에서매우강력한세균요소분해효소억제효과를가진다. 21 향후헬리코박터치료에가능한분자들을 Table 1에, 생체내에서가능한여러식물들을 Table 2에제시하였다. 19 많은연구에서새로운치료의표적 ( 예, 박테리아단백질, 기전, 성장과군집등에필요한유전자 ) 을목표로한연구들이있다. 따라서미래에는헬리코박터에보다강력한약제들이사용될수있을것이다. Table 1. New Molecules with Helicobacter pylori Activity Molecules MIC 90 value (mg/l) ph activity Cla-R/Met-R Arylthiazole derivative NA NA/NA Benzimidazole derivatives Y NA/NA BAS NA Yes/yes I-valnemulin NA Yes/yes Mupirocin NA/NA Polycyclic compound NA NA/NA Pyloricidin (A, B, and C) NA NA/NA Rifampin NA Yes/yes MIC 90, minimal inhibitory concentration; Cla-R, efficacy towards clarithromycin resistant strains; Met-R, efficacy towards metronidazole resistant strains; NA, not available. (Adapted from the article of Fiorini et al. Clin Exp Gastroenterol 2012;5: ) 233

3 Korean J Helicobacter Up Gastrointest Res: Vol 12, No 4, December 일순차요법 (sequential therapy) 최근관심이높아지는것은 10일순차요법으로, 22,23 5일간의 PPI 와 amoxicillin 을 5일투약하고, 이후나머지 clarithromycin 과 metronidazole 을투여하는것이다. 이러한복잡한치료의이적근거는 amoxicilline 이약해진세균의세포벽을치료초기에약화시켜서 clarithromycin 이세포리보좀에결합하는것을억제해 clarithromycin 의효과를극대화하는것이다 년도메타분석에서도순차요법이표준삼제요법보 Table 2. Some Plant Extracts with Potential Anti-Helicobacter pylori Activity in vitro Plant source Source or molecule MIC 90 (mg/l) Barringtonia acutangola Leaf 25 Cassia grandis Leaf 50 Cleome viscosa Leaf 50 Cycas siamensis Leaf 100 Hypericum perforatum L. Hyperforin 15.6~31.2 Hyptis fasciculata Cirsilineol/Cirsimaritin 3.2~6.3 Kaempferia galanga Rhizome 25 Litsea elliptica Leaf 100 Maleleuca quinquenervia Leaf 100 Mallotus phillippinensis Rottlerin 3.12~6.25 Myristica fragrans Aril 12.5 Myristica fragrans Leaf 50 Pistacla lentiscus Triterpenic acids Pouzolzia pentandra Leaf 100 Syzygium aromaticum Leaf 50 Vitis vinifera Resveratrol 6~12.5 Xanthium brasilicum Xanthanolide 13.2~250 Zingiber officinale Rhizome 0.78~12.5 MIC 90, minimal inhibitory concentration. (Adapted from the article of Fiorini et al. Clin Exp Gastroenterol 2012;5: ) 다우월함이입증되어표준치료로될가능성을제시하였다. 25 국내에서도최근 10일순차요법과표준 3제요법을비교한전향적무작위대조연구에서 10일순차요법이표준치료에비해우월성이입증되었고, 후향적연구에서도 ITT, PP 분석모두 91.8% 높은제균율을보여준다 (Table 3) 그러나, 약물부작용이증가하고, 2차치료에대안이불확실한단점이있어일차표준치료를대치할지여부는신중한고려가필요하다. 5. 동시요법 (concomitant therapy) 동시요법은 PPI와 amoxicillin, clarithromycin, metronidazole 을동시에투약하는것이다. 31 이는 10년전에처음소개되었으며, 최근 270명을대상으로한국내연구에서 PP 분석에서표준삼제요법에서 86.1% 의제균율, 동시요법에서 91.4% 의제균율을보고하였다. 31 그러나, 경미한부작용은동시요법 (35.6%) 에서표준삼제요법 (25.2%) 보다더많이보고되는경향을보였다 (P =0.09). 또다른 9개의메타분석에서도 7일간의동시요법을했을때, ITT 분석에서 90%, PP 분석에서 93% 의제균율을보여주었다. 32 5개의무작위대조연구에서표준치료에비해메타분석에서동시요법이우월하였다 (OR, 2.86; 95% CI, ). 따라서, 앞으로동시요법은헬리코박터제균치료의일차치료의표준치료의대안으로사용될가능성이있다. 6. 맞춤개별화치료 (tailored therapy) 헬리코박터제균성공에는적절한위산억제와헬리코박터균주의내성여부가중요하기때문에 PPI 를기본으로하는표준삼제요법에서 CYP2C19 유전자형은제균성공을판가름하는중요한인자가될수있다. 33,34 그러나, 아직까지국내에서 CYP2C19 유전자형을임상에서검사하기는쉽지않다. 헬리코 Table 3. Helicobacter pylori Eradication Rates in the Sequential Therapy and PPI-based Triple Therapy of Korean Studies Studies Study designs 10-day sequential therapy PPI-based triple therapy P value ITT analysis Oh et al. 26 Prospective RCT 79.3% (92/116) 63.0% (82/130) Chung et al. 27 Prospective RCT 75.9% (60/79) 58.7% (47/80) 0.01 Park et al. 28 Prospective RCT 77.8% (126/162) 62.2% (102/164) Choi et al. 29 Prospective RCT 77.9% (60/77) 71.6% (58/81) Kwon et al. 30 Retrospective study 91.8% (90/98) NA NA PP analysis Oh et al. 26 Prospective RCT 81.9% (91/111) 64.5% (82/127) Chung et al. 27 Prospective RCT 86.8% (59/68) 67.6% (46/68) 0.01 Park et al. 28 Prospective RCT 87.9% (116/132) 76.0% (95/125) Choi et al. 29 Prospective RCT 85.7% (60/70) 76.6% (58/76) Kwon et al. 30 Retrospective study 91.8% (89/97) NA NA PPI, proton pump inhibitor; ITT, intention-to-treat; RCT, randomized controlled trial; NA, not available; PP, per protocol. 234

4 Hyun Joo Song: Future of Helicobacter pylori Eradication-New Trials 박터제균치료의효과를극대화하기위하여개인의유전적다형성, 연령등다른인구학적요소들을고려한개별화된맞춤형치료가생길것이다. 결 생체내에서단독적으로헬리코박터제균에효과적인항생제는매우드물어여러가지약물을혼합해서순차적또는동시투여하는것이다. 현재표준치료이외에도가능한치료는 levofloxacin 을이용한치료와 Saccharomyces boulardii 와 Lactobacillus 보조요법을생각해볼수있다. 새로운분자들이체외에서 clarithromycin 과 metronidazole 에내성있는헬리코박터에매우높은살균효과를가질수있어, benzimidazolederivatives, polycyclic compounds, pyloricidin, arylthiazole analogues 등에기대를걸어본다. 많은연구에서새로운치료적목표로헬리코박터제균에대한시도들은지속되고있다. 또한개인의성향에맞는맞춤형치료도도입될것이다. 위암을예방하고항생제내성을막기위한새로운치료에대한연구는지속되어야할것이다. 참고문헌 1. Sonnenberg A, Lash RH, Genta RM. A national study of Helicobactor pylori infection in gastric biopsy specimens. Gastroenterology 2010;139: Gasparetto M, Pescarin M, Guariso G. Helicobacter pylori eradication therapy: current availabilities. ISRN Gastroenterol 2012; 2012: 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: Kim SY, Jung SW. Helicobacter pylori eradication therapy in Korea. Korean J Gastroenterol 2011;58: 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: O'Connor A, Gisbert JP, McNamara D, O'Morain C. Treatment of Helicobacter pylori infection Helicobacter 2011;16 Suppl 1: Molina-Infante J, Perez-Gallardo B, Fernandez-Bermejo M, et al. Clinical trial: clarithromycin vs. levofloxacin in first-line triple and sequential regimens for Helicobacter pylori eradication. Aliment Pharmacol Ther 2010;31: Romano M, Cuomo A, Gravina AG, et al. Empirical levofloxacin-containing versus clarithromycin-containing sequential therapy for Helicobacter pylori eradication: a randomised trial. Gut 2010;59: Cheng H, Hu FL, Zhang GX, et al. Levofloxacin-based triple therapy for first-line Helicobacter pylori eradication treatment: a multi-central, randomized, controlled clinical study. Zhonghua Yi Xue Za Zhi 2010;90: Lee JH, Hong SP, Kwon CI, et al. the efficacy of levofloxacin based triple therapy for Helicobacter pylori eradication. Korean J Gastroenterol 2006;48: Kim JM. Antibiotic resistance of Helicobacter pylori isolated from Korean patients. Korean J Gastroenterol 2006;47: Kim JY, Kim NY, Kim SJ, et al. Regional difference of antibiotic resistance of Helicobacter pylori strains in Korea. Korean J Gastroenterol 2011;57: Jung HS, Shim KN, Baik SJ, et al. Efficacy of levofloxacin-based triple therapy as second-line Helicobacter pylori eradication. Korean J Gastroenterol 2008;51: Song MJ, Park DI, Park JH, et al. The effect of probiotics and mucoprotective agents on PPI-based triple therapy for eradication of Helicobacter pylori. Helicobacter 2010;15: Szajewska H, Horvath A, Piwowarczyk A. Meta-analysis: the effects of Saccharomyces boulardii supplementation on Helicobacter pylori eradication rates and side effects during treatment. Aliment Pharmacol Ther 2010;32: Medeiros JA, Gonçalves TM, Boyanova L, et al. Evaluation of Helicobacter pylori eradication by triple therapy plus Lactobacillus acidophilus compared to triple therapy alone. Eur J Clin Microbiol Infect Dis 2011;30: Choi JY, Shim KN, Kong KA, et al. Meta-analysis: the effect of lactobacillus supplementation on Helicobacter pylori eradication rates and side effects during treatment. Korean J Helicobacter Up Gastrointest Res 2012;12: Yaşar B, Abut E, KayadıbıH, et al. Efficacy of probiotics in Helicobacter pylori eradication therapy. Turk J Gastroenterol 2010;21: Fiorini G, Zullo A, Gatta L, et al. Newer agents for Helicobacter pylori eradication. Clin Exp Gastroenterol 2012;5: Zullo A, Hassan C, Campo SM, Morini S. Evolving therapy for Helicobacter pylori infection. Exp Opin Ther Patents 2004;14: Zullo A, Hassan C, Eramo A, Morini S. Helicobacter pylori therapy: what is coming? Expert Opin Ther Patents 2006;16: Moayyedi P. Sequential regimens for Helicobacter pylori eradication. Lancet 2007;370: Zullo A, De Francesco V, Hassan C, Morini S, Vaira D. The sequential therapy regimen for Helicobacter pylori eradication: a pooled-data analysis. Gut 2007;56: De Francesco V, Margiotta M, Zullo A, et al. Clarithromycin-resistant genotypes and eradication of Helicobacter pylori. Ann Intern Med 2006;144: Jafri NS, Hornung CA, Howden CW. Meta-analysis: sequential therapy appears superior to standard therapy for Helicobacter pylor infection in patients naive to treatment. Ann Intern Med 235

5 Korean J Helicobacter Up Gastrointest Res: Vol 12, No 4, December ;148: Oh HS, Lee DH, Seo JY, et al. Ten-day sequential therapy is more effective than proton pump inhibitor-based therapy in Korea: a prospective, randomized study. J Gastroenterol Hepatol 2012;27: Chung JW, Jung YK, Kim YJ, et al. Ten-day sequential versus triple therapy for Helicobacter pylori eradication: A prospective, open-label, randomized trial. J Gastroenterol Hepatol 2012;27: Park HG, Jung MK, Jung JT, et al. Randomised clinical trial: a comparative study of 10-day sequential therapy with 7-day standard triple therapy for Helicobacter pylor infection in naïve patients. Aliment Pharmacol Ther 2012;35: Choi WH, Park DI, Oh SJ, et al. Effectiveness of 10 day-sequential therapy for Helicobacter pylori eradication in Korea. Korean J Gastroenterol 2008;51: Kwon JH, Lee DH, Song BJ, et al. Ten-day sequential therapy as first-line treatment for Helicobacter pylori infection in Korea: a retrospective study. Helicobacter 2010;15: Kim SY, Lee SW, Hyun JJ, et al. Comparative study of Helicobacter pylori eradication rates with 5-day quadruple "concomitant" therapy and 7-day standard triple therapy. J Clin Gastroenterol 2012 May 29. [Epub ahead of print] 32. Gisbert JP, Calvet X. Review article: non-bismuth quadruple (concomitant) therapy for eradication of Helicobater pylori. Aliment Pharmacol Ther 2011;34: Sugimoto M, Furuta T, Shirai N, et al. Treatment strategy to eradicate Helicobacter pylori infection: impact of pharmacogenomics-based acid inhibition regimen and alternative antibiotics. Expert Opin Pharmacother 2007;8: Furuta T, Graham DY. Pharmacologic aspects of eradication therapy for Helicobacter pylori infection. Gastroenterol Clin North Am 2010;39:

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untitled Korean J Gastroenterol Vol. 58 No. 2, 67-73 http://dx.doi.org/10.4166/kjg.2011.58.2.67 REVIEW ARTICLE 국내 Helicobacter pylori 의제균치료 김승영, 정성우 고려대학교의과대학내과학교실 Helicobacter pylori Eradication Therapy in Korea