Future Trends of Helicobacter pylori Eradication Therapy in Korea

Ju Yup Lee; Nayoung Kim

doi:10.4166/kjg.2014.63.3.158

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Lee and Kim: Future Trends of Helicobacter pylori Eradication Therapy in Korea

Review Article

Korean J Gastroenterol 2014;63(3):158-170.

Published online: 4 October 2014

DOI: https://doi.org/10.4166/kjg.2014.63.3.158

Future Trends of Helicobacter pylori Eradication Therapy in Korea

Ju Yup Lee¹, Nayoung Kim^1,²

¹Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea

²Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea

Correspondence to: Nayoung Kim, Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-ro, 173beon-gil, Bundang-gu, Seongnam 463-707, Korea. Tel: +82-31-787-7008, Fax: +82-31-787-4051, E-mail: nayoungkim49@empas.com

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.

Abstract

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.

Keywords: Helicobacter pylori, Guidelines, Treatment, Prevention

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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 2004–2005 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.^16–18 (C) Prevalence (using urine antibody or serum IgG antibody) of H. pylori in 1992, 2002–2006, and 2007–2011 in Japan.^19–21 Reused from the article of Shiota, et al. (Expert Rev Gastroenterol Hepatol 2013;7:35–40)²¹ with original copyright holder' s permission.

Fig. 2.

The mean intention-to-treat (ITT) eradication rate for sequential therapy reported after 2008 in Europe (Italy,^74–79 Spain^78,79), Korea,⁸² and Asia (China, Taiwan, India, and Iran).⁸²

Table 1.

Antibiotics Resistance Rates (%) for Helicobacter pylori Infection around the World

Antibiotics	USA (1998–2002)²⁹	Europe (2008–2009)³⁰			Japan (2004–2005)²⁸	China (2010–2012)⁴¹
Antibiotics	USA (1998–2002)²⁹	Northern	Central/Western	Southern	Japan (2004–2005)²⁸	China (2010–2012)⁴¹
Amoxicillin	0.9	<0.7	<0.7	<0.7	0.08	0.1
Clarithromycin	12.9	7.7	18.7	21.5	27.7	21.5
Metronidazole	25.1	28.6	43.8	29.7	2.1	94.5
Tetracycline	−	<0.9	<0.9	<0.9	−	−
Ciprofloxacin	−	−	−	−	−	13.7
Levofloxacin	−	7.7	18.6	13.1	15.0³⁴	20.6

Table 2.

Antibiotic Resistance Rates for Helicobacter pylori in Korea

Antibiotics	Seoul								Gyeonggi			Gyeonggi Gangwon Busan
Antibiotics	1987⁴²(n=34)	1994⁴²(n=36)	1994⁴⁴(n=63)	1995⁴⁴(n=130)	1996⁴⁴(n=129)	1997⁴⁴(n=69)	1998–1999⁴⁴(n=65)	2003⁴²(n=65)	2003–2005⁶(n=69)	2006–2008⁶(n=202)	2009–2013⁶(n=204)	2008⁴⁵(n=40)	2008⁴⁵(n=40)	2008⁴⁵(n=19)
Amoxicillin	0	5.6	0	0	0	0	0	18.5	7.2	7.4	17.2	12.5	10.0	9.1
Clarithromycin	0	2.8	4.8	4.6	3.9	11.6	7.7	13.8	23.2	27.2	37.3	32.5	12.5	26.3
Metronidazole	52.9	61.1	33.3	38.5	42.6	40.6	47.7	66.2	34.8	23.8	35.8	25.0	10.0	19.2
Tetracycline	5.9	0	3.0	6.9	4.7	2.9	7.7	12.3	8.7	11.9	10.8	12.5	7.5	15.2
Ciprofloxacin	0	13.9	−	−	−	−	−	33.8	17.4	29.7	38.2	40.0	22.5	30.0
Levofloxacin	0	0	−	−	−	−	−	21.5	5.8	23.3	37.7	22.5	22.5	23.2
Moxifloxacin	0	0	−	−	−	−	−	21.5	5.8	23.3	37.3	22.5	22.5	23.2

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).

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	5) Functional dyspepsia (2A)	Prior to NSAIDs therapy/additional to
	1) Following EMR for EGC	Evidence level B	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 aspirin (2C)	Idiopathic thrombocytopenic purpura
	3) MALToma	aspirin (2C)	Iron deficiency anemia
			Vitamin B12 deficiency
First-line	PPI (standard dose b.i.d.)	PPI (standard dose b.i.d.)	Prevalence of Clari-R <20%: PPI-Clari-
regimen	Clarithromycin (200–400 mg b.i.d)	Clarithromycin (500 mg b.i.d)	amoxicillin/metronidazole
	Amoxicillin (750 mg b.i.d.)	Amoxicillin (1,000 mg b.i.d.)	Prevalence of Clari-R >20%: bismuth
			quadruple therapy or sequential/
			concomitant therapy
Duration	7 days	7–14 days	7 or 10–14 days

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 guideline⁴⁷: 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 guideline⁴⁸: 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.

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 10–14 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 10–14 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).

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)
First author	Study years	RCT (n)	Patient (n)	Region	SQT	STT	vs. STT	vs. 7-day STT	vs. 10-day STT	vs. 14-day STT
Jafri⁷¹	−2007	10	2,747	Italy	93.4	76.9	1.71 (1.64–1.77)	1.26 (1.20–1.33)	1.35 (1.24–1.53)	−
Gatta⁷²	−2008	13	3,006	Italy	91.0	75.7	2.99 (2.47–3.62)	3.21 (2.61–3.97)	2.93 (1.95–4.39)	−
Tong⁷³	−2008	11	2,883	Italy	93.3	76.9	−	1.23 (1.19–1.27)	1.16 (1.10–1.23)	−
Gatta⁸⁰	⁰ 2003–2013	46	5,666	Global	84.3	76.0	−	1.21 (1.17–1.25)	1.11 (1.04–1.19)	1.00 (0.94–1.06)
Yoon⁸²	2008–2013	17	3,419	Asia	81.8	74.3	1.10 (1.04–1.16)	1.15 (1.09–1.22)	1.05 (0.93–1.20)	1.06 (1.01–1.11)
Kim⁸¹	2008–2012	6	1,759	Korea	79.4	68.2	1.76 (1.40–2.21)	−	−	−

RCT, randomized controlled trial; ITT, intention-to-treat; SQT, sequential therapy; STT, standard triple therapy.

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