Approximately half of the world's population is infected by Helicobacter pylori [1], which causes various gastrointestinal diseases including gastritis, peptic ulcer, gastric mucosaassociated lymphoid tissue lymphoma, and gastric cancer [23]. Korean guidelines, which were revised in 2013, by the Korean College of Helicobacter and Upper Gastrointestinal Research strongly recommend that H. pylori should be eradicated in patients with peptic ulcer disease, gastric MALT lymphoma, endoscopically treated early gastric cancer, and immune thrombocytopenic purpura [4].

Identification of optimal regimen of H. pylori eradication has been a challenge for gastroenterologists. Twenty years ago, one comparative study showed that proton pump inhibitor (PPI)-based triple therapy, that consisted of PPI, amoxicillin, and metronidazole, had superior efficacy for H. pylori eradication among various regimens based on PPI, bismuth, amoxicillin, and metronidazole [5]. In addition, conventional triple therapy, that consists of PPI, amoxicillin, and clarithromycin, has been widely used in Korea because of the high resistance rate of H. pylori against metronidazole [467]. This conventional triple therapy for 7–14 days is also a world-wide choice for H. pylori eradication [89]. However, eradication of conventional triple therapy has decreased over the past 10 years [1011], caused by resistance against clarithromycin [12]. Alternatively, many eradication regimens including sequential therapy, concomitant therapy, and hybrid therapy have been suggested [4]. Despite of the insufficient eradication rate of the conventional triple therapy, the current Korean guideline still recommends conventional triple therapy as a first-line therapy for H. pylori infection because superior efficacy of alternative regimens over the conventional triple therapy has not been fully evaluated [4]. Recently, however, the Maastricht V/Florence Consensus Report stated that PPI-clarithromycin-containing triple therapy without prior susceptibility testing should be abandoned when the clarithromycin resistance rate in the regions is more than 15% [13]. In other words, alternative regimens should be considered in the clarithromycin-resistant H. pylori prevalent regions when treating H. pylori infection without prior susceptibility test. Understanding H. pylori eradication regimens will help select drugs in the management of H. pylori infection.

PPIs have two major roles in the eradication therapy; one is reducing gastric acid secretion, and the other is increasing bioavailability and activities of antibiotics [14]. In addition, gastric acid secretion is not sufficiently inhibited in extensive metabolizers of PPIs. Therefore, many clinicians wondered whether more potent PPIs would lead to a higher eradication rate. In Taiwan, esomeprazole-based triple therapy showed superior efficacy of H. pylori eradication rate compared to omeprazole in the extensive metabolizer subgroup [15]. However, significant difference was not observed between esomeprazole and omeprazole, in all patients including extensive and poor metabolizers. A randomized-controlled trial in Korea also showed that double-dose of new-generation PPIs including esomeprazole and rabeprazole did not affect the H. pylori eradication rate [16], compared with 20 mg of omeprazole twice daily. Relatively low proportion of extensive metabolizers in Korea may be a reason for the insignificant difference between different PPIs in terms of H. pylori eradication rate. Although several PPIs are not approved for the purpose of H. pylori eradication therapy currently, by the Ministry of Food and Drug Safety in Korea, all types of PPIs may be effective for H. pylori eradication.

A remarkable thing about H. pylori eradication therapy is use of potassium-competitive acid blockers (P-CABs) instead of PPIs. P-CABs inhibit gastric hydrogen/potassium-ATPase in a potassium-competitive and reversible manner [17]. Because P-CAB is highly accumulated and slowly excreted from gastric tissue, it has a potent and a long-lasting anti-secretory effect on gastric acid [18]. In Japan, triple therapy based on vonoprazan, a novel P-CAB, showed favored eradication rate compared to lansoprazole-based triple therapy [19]. The eradication rate was 92.6% (95% confidence interval [CI] 89.2% to 95.2%) and 75.9% (95% CI 70.9% to 80.5%) in vonoprazan- and lansoprazole-based triple therapies, respectively. Although Korean studies are lacking now, P-CAB-based therapy may be one potential option for H. pylori eradication. However, resistance against antibiotics remains a matter for concern. In the study on vonoprazan-based triple therapy, eradication rate was still insufficient in patients with clarithromycin-resistant H. pylori infection [192021]. Although P-CAB-based therapy may be a superior regimen over PPI-based therapy, it cannot be recommended in the presence of clarithromycin-resistant infections [22].

Conventional triple therapy usually consists of standard dose of PPI, 1 g of amoxicillin, and 500 mg of clarithromycin, twice daily [4]. As mentioned in the Introduction, metronidazole as a first-line therapy has not been recommended in Korea because of the high resistance of H. pylori [4]. The resistance rate of H. pylori against metronidazole in Korea has increased from 33.3% in 1994, to 47.7% in 1999, to 66.2% in 2003 [23].

In the rank probability analysis of the world-wide network meta-analysis, conventional triple therapy for 7 days showed relatively good tolerability among various regimens; however, ranking of eradication rate was very poor [24]. Many years ago, prolonged duration of triple therapy was effective for increasing H. pylori eradication rate. A randomized-controlled study published in 2001 demonstrated that eradication rate was 74.4%, 80.2%, and 91.9% in the triple therapy for 7 days, 10 days, and 14 days, respectively. However, the high eradication rate of 14 days-triple therapy seems to decrease as times goes on. A randomized-controlled study published in 2007 indicated no difference of eradication rate between 7 days-regimen and 14 days-regimen (intention-to-treat [ITT] analysis: 71.2% and 75.5%, respectively) [25]. Another study published in 2012 also demonstrated no significant difference among 7 days-, 10-days, and 14-days regimens (ITT analysis: 70.4%, 74.7%, and 80.0% respectively, P=0.244) [26]. Although the current guideline still recommends the conventional triple therapy for 7 to 14 days as first-line H. pylori eradication therapy, clinicians should be cautious for treating H. pylori infection with the conventional triple therapy.

In order to increase the conventional triple therapy, various supplements, including probiotics and mucoprotective agents have been tried [2728293031]. Overall, probiotics seemed to have additive effect on H. pylori eradication. One study comparing eradication rate between the conventional triple therapy for 7 days and that with probiotics (Bacillus subtilis [2.5×10⁹ colony-forming unit [CFU]/g] and Streptococcus faecium [2.25×10¹⁰ CFU/g]) for 8 weeks showed the superior efficacy of probiotics-included regimen (ITT analysis: with probiotics vs. without probiotics, 83.5% vs. 73.3%, P=0.020) [27]. Another study demonstrated that eradication rate of the conventional triple therapy for 7 days with Will yogurt®, which contains probiotics (Lactobacillus acidophilus [>10⁵ CFU/mL], Lactobacillus casei [>10⁵ CFU/mL], Bifidobacterium longum [>10⁶ CFU/mL], and Streptococcus thermophiles [>10⁸ CFU/mL]) for at least 3 weeks tended to be higher than the conventional triple therapy only (ITT analysis: 79.2% vs. 72.1%, P=0.124) [28]. Another study also showed the superiority of eradication rate in the probiotics group (Saccharomyces boulardii [3×10¹⁰ CFU/g] for 4 weeks) compared to the conventional triple therapy only group (ITT analysis: 80.0% vs. 71.6%, P=0.012) [30]. Probiotics-included regimens can be helpful for increasing eradication rate of conventional triple therapy. However, prolonged duration of H. pylori eradication may be a disadvantage of this strategy.

In contrast to the results of probiotics, mucoprotective agent seemed to be less effective. In two randomized-controlled trials comparing between conventional triple therapy only vs. conventional triple therapy with ecabet sodium (gliptide®), there was no difference of eradication rate between the groups (ITT analysis: 72.1% vs. 78.9%, P=0.204; 81.4% vs. 86.2%, P=0.159) [3031]. Although there was no significant difference on ITT analyses, per protocol (PP) analysis of one study showed superiority of mucoprotective agent-included therapy (PP analysis: conventional triple therapy only vs. conventional triple therapy with ecabet sodium, 78.8% vs. 88.6%, P=0.044) [29]. Given that mucoprotective agent was administered for only 7 days unlike probiotics, prolonged medication of mucoprotective agent may be helpful for increasing the eradication rate of H. pylori.

Sequential therapy was first introduced by Zullo et al. in 2000 [32]. Standard sequential therapy regimen consists of two phases of treatment. For the first 5 days (or 7 days), standard dose of PPI and 1 g of amoxicillin are administered twice daily. Thereafter, standard dose of PPI, 500 mg of clarithromycin, and 500 mg of metronidazole (or tinidazole) are administered twice daily for the last 5 days (or 7 days). Sequential therapy has been suggested because of inoculum effect and efflux channel of clarithromycin [3334]. In the first phase of treatment, amoxicillin is aimed to lower the bacterial load in the stomach to improve the efficacy of the immediately subsequent short course of triple therapy that consists of PPI, clarithromycin, and metronidazole [33]. It has been known that amoxicillin is not affected by bacterial factors including CagA status and infection density [33]. In addition, amoxicillin in the first phase of treatment may prevent the development of efflux channels by damaging the cell wall of H. pylori [35]. This may help to improve the efficacy of clarithromycin in the second phase of the treatment.

In Korea, the first study on comparison between sequential therapy vs. conventional triple therapy was published in 2008 [36]. In this study standard sequential therapy for 10 days was compared to conventional triple therapy for 7 days. Unfortunately, it did not show difference of eradication rate between the two regimens because of small sample size (ITT analysis: sequential vs. triple therapy, 77.9% vs. 71.6%, P=0.361). However, many investigators have been interested in sequential therapy. Actually, head-to-head comparisons between conventional triple and sequential therapies were the most frequently performed designs in Korea among the clinical trials on first-line H. pylori eradication regimens. In 2011, sequential therapy for 10 days was shown to be superior to conventional triple therapy for 14 days (ITT analysis: 85.9% vs. 75.0%, P=0.006) [37]. In 2012, three studies were published, and two of them demonstrated superior efficacy of sequential therapy compared to conventional triple therapy for 7 days (ITT analysis: 62.2% vs. 77.8%, P=0.002; 63.0% vs. 79.3%, P=0.005) [3839], while the remaining one did not show statistical difference of eradication rate among sequential therapy and various triple therapy regimens (ITT analysis: sequential therapy vs. 7 days-triple therapy vs. 10 days-triple therapy vs. 14 days-triple therapy, 75.6% vs. 70.4% vs. 74.7% vs. 80.0%, P=0.416) [26]. In 2016, a nationwide multi-center randomized-controlled trial showed that sequential therapy had better eradication rate than conventional triple therapy as a first-line treatment of H. pylori infection (ITT analysis: 82.4% vs. 70.8%, P=0.001) [40].

Overall, sequential therapy seemed to be better than conventional triple therapy in terms of eradication rate. A meta-analysis in Korea also demonstrated that eradication rate of sequential therapy was superior to that of conventional triple therapy (79.7% vs. 68.1%, P<0.001). However, a 79.7% eradication rate in sequential therapy is still unacceptable according to the report card for scoring the outcome (the reports when scoring the outcomes) of anti-H. pylori therapy [21]. On ITT analysis, at least a 85% eradication rate is required to adopt the regimen for H. pylori eradication. In addition, some investigators suggested that superior efficacy of sequential therapy may be caused not by sequential use of drugs but use of three antibiotics including amoxicillin, clarithromycin, and metronidazole (or tinidazole) [41]. For these reasons, the regimen that consisted of three antibiotics and PPI, namely concomitant therapy, was introduced.

Concomitant therapy consists of all drugs given in sequential therapy, which are standard dose of PPI, 1 g of amoxicillin, 500 mg of clarithromycin, and 500 mg of metronidazole. All drugs are administered twice daily simultaneously. However, durations of concomitant therapy vary from 5 days to 14 days. Until recently, no consensus regarding the optimal duration was established.

In the world-wide network meta-analysis, concomitant therapy was ranked best for eradication rate among various regimens including sequential therapy [24]. However, Korean data do not support this worldwide study. In 2013, there was no difference of eradiation rate between 14 days-sequential therapy and 14 days-concomitant therapy (ITT analysis: 75.6% vs. 80.8%, P=0.423) [42]. Two studies published in 2016 also did not show any difference of eradication rate between sequential and concomitant therapy (ITT analysis: 10 days-sequential vs. 10 days-concomitant therapy, 70.6% vs. 77.8%, P=0.140; 10 days-sequential vs. 14 days-sequential vs. 10 days-concomitant vs. 14 days concomitant therapy, 77.6% vs. 73.8% vs. 75.6% vs. 77.9%, P=0.915) [4344].

Judging from previously reported Korean randomized-controlled trials, it seems that there was no difference of eradication rate between sequential and concomitant therapies. However, number of studies may be insufficient for reaching a definitive conclusion. In addition, indirect evidence as well as direct evidence should be considered to fully analyze the comparison. For example, there are many studies on the comparison between conventional triple therapy and sequential therapy. In addition, studies comparing conventional triple therapy with concomitant therapy also exist. Based on these studies, indirect evidence between sequential therapy and concomitant therapy can be induced. Because indirect evidence provides additional information upon direct evidence, it may be helpful for increasing statistical power and improving precision of estimates. Korean network meta-analysis on H. pylori eradication may be needed for clarifying the comparative efficacy of concomitant therapy.

A modified sequential therapy, namely hybrid therapy, was also introduced for increasing eradication rate of H. pylori. It starts with a dual regimen of standard dose of PPI and 1 g of amoxicillin twice daily for 5 days (or 7 days) like sequential therapy. However, quadruple therapy that consists of standard dose of PPI, 1 g of amoxicillin, 500 mg of clarithromycin, and 500 mg of metronidazole twice daily for the next 5 days (or 7 days) is followed. Prolonged administration of amoxicillin is a characteristic of hybrid therapy compared to sequential therapy. It also resembles 10 days- or 14 days-concomitant therapy; however, clarithromycin and metronidazole are not included in the first 5 or 7 days of the treatment.

There are two randomized controlled trials on hybrid therapy compared to either sequential or concomitant therapy in Korea [1345]. In one study that compared eradication rate of H. pylori between 14 days-hybrid therapy and 14 days-sequential therapy, there was no statistical difference (ITT analysis: 81.1% vs. 79.8%, P=0.821) [45]. In addition, one study between 10 days-hybrid therapy vs. 10 days-concomitant therapy did not show any difference of H. pylori eradication rate (ITT analysis: 78.8% vs. 78.6%, P=0.943) [13]. Overall, hybrid therapy seemed to have superiority to neither sequential nor concomitant therapy in terms of H. pylori eradication rate.

Traditional H. pylori eradication regimens include PPI, amoxicillin, clarithromycin, tinidazole (or metronidazole), and bismuth subcitrate. Recently, however, it has been known that quinolone, that inhibits deoxyribonucleic acid gyrase, is effective in the treatment of H. pylori infection [464748]. Additionally, many studies support that quinolone-based sequential therapy is effective in an area with >15% prevalence of clarithromycin resistant H. pylori strains [4950]. Quinolone-based sequential therapy consists of two phases of treatment like standard sequential therapy. For the first 5 days (or 7 days), standard dose of PPI and 1 g of amoxicillin are administered twice daily. Thereafter, standard dose of PPI twice daily, 500 mg of metronidazole (or tinidazole) twice daily, and quinolone (i.e., 400 mg of moxifloxacin once daily or 250 mg of levofloxacin twice daily) are administered for the last 5 days (or 7 days).

Until recently, quinolone-based sequential therapy is the most promising regimen in Korea. One study between moxifloxacin-based sequential therapy for 14 days vs. standard sequential therapy for 14 days showed superiority of moxifloxacin-based sequential therapy in terms of eradication rate (91.3% vs. 71.6%, P=0.001) [51]. In addition, eradication rate of moxifloxacin-based sequential therapy for 14 days was higher than that of hybrid therapy for 14 days (91.4% vs. 79.2%, P=0.004) [52]. Although data of eradication rate of quinolone-based sequential therapy compared to concomitant therapy is lacking now, indirect estimate may support superior efficacy of quinolone-based sequential therapy over concomitant therapy given that the eradication rate of concomitant therapy was similar to that of sequential or hybrid therapies.

However, one study comparing eradication rate between 10 days-standard sequential therapy vs. 10 days-levofloxacin-based sequential therapy showed no statistical difference (79.0% vs. 78.0%, P=0.863). It is not certain that the discrepant results were caused by type of quinolone (moxifloxacin vs. levofloxacin) or duration of treatment (14 days vs. 10 days). More randomized controlled trials in this issue may be needed for reaching a definitive conclusion.

Another concern of quinolone-based regimen in Korea is the potential drug resistance of Mycobacterium tuberculosis, because quinolone is one of the medications for tuberculosis, which is highly endemic in Korea. Additionally, latent tuberculosis infection is also prevalent in Korea. The positive results of tuberculin skin test and whole-blood interferon gamma assay was 51-52% and 4-14%, respectively [5354], in the young general population in Korea. If quinolone-based regimen is adopted as a primary treatment regimen for H. pylori infection, there may be a chance of increasing quinolone resistance of M. tuberculosis. Careful consideration of this issue may be needed for adopting quinolone-based sequential therapy as a first-line eradication regimen for H. pylori infection.

Bismuth-containing quadruple therapy consists of standard dose of PPI b.i.d., 120 mg of bismuth q.i.d, 500 mg of metronidazole t.i.d., and 500 mg of tetracycline q.i.d. for 7 to 14 days. Traditionally, bismuth-containing quadruple therapy has been generally used for the second-line regimen of H. pylori eradication [555657]. Although the Korean guideline suggested that bismuth-containing quadruple therapy may be an alternative first-line regimen if clarithromycin-resistance is suspected, evidence of bismuth-containing quadruple therapy as a first-line regimen is insufficient in Korea. The first randomized-controlled trial comparing bismuth-containing quadruple therapy with conventional triple therapy as a first-line regimen was published in 2005 [58]. It did not show difference of eradication rate (ITT analysis: 7 days-bismuth containing quadruple vs. 7 days-conventional triple therapy, 71.6% vs. 78.7%, P=0.424). Recently, 14 days-bismuth-containing quadruple therapy was compared to 10 days-sequential therapy in a multi-center, randomized-controlled trial [59]. In this study, there was no difference of eradication rate between the two regimens (ITT analysis: bismuth-containing quadruple vs. sequential therapy, 68.7% vs. 74.9%, P=0.240). In addition, PP analysis showed that eradication rate of bismuth-containing quadruple therapy tended to be lower than that of sequential therapy (76.5% vs. 84.2%, P=0.099).

Given that clarithromycin is not included in the bismuth-containing quadruple therapy, this regimen may be an alternative first-line regimen in regions where clarithromycin-resistant H. pylori is prevalent. However, more studies are required for clarifying the effectiveness of bismuth-containing quadruple therapy as a first-line treatment of H. pylori infection.

Currently, various H. pylori eradication regimens are available (Table 1). Based on the randomized-controlled trials in Korea, conventional triple therapy is unacceptable for the first-line therapy without prior susceptibility test because of the high clarithromycin-resistance rate. Sequential therapy, hybrid therapy, and concomitant therapy seemed to be more effective than the conventional triple therapy; however, eradication rates of these regimens are also unsatisfactory considering the report card for scoring the outcome (the reports when scoring the outcomes) of anti-H. pylori therapy [21]. Current evidence supports the quinolone-based sequential therapy may be a good choice as first-line therapy in Korea. However, this narrative review cannot provide a definitive conclusion because there are many head-to-head trials among various regimens, and only direct evidence was considered here. Indirect estimates should be considered for clarifying the comparative efficacy of various H. pylori eradication regimens. Network meta-analysis based on Korean randomized-controlled trials may be helpful for guiding selection of eradication regimen in patients with H. pylori infection in Korea.