Chinese Medical Journal 2014;127(3):568-573:10.3760/cma.j.issn.0366-6999.20132708
Helicobacter pylori infection: an overview in 2013, focus on therapy

Cui Rongli and Zhou Liya

Keywords
Helicobacter pylori; antibiotic resistance; prevalence; therapy
Abstract
Objective This article aimed to review the incidence of Helicobacter pylori (H. pylori) infection and its therapy.
Datasources Relevant articles published in English were identified by searching in PubMed from 2000 to 2013, with keywords “H. pylori”. Important references from selected articles were also retrieved from Elsevier, Wiley, EBSCO, and SPRINGER. The Chinese articles published were searched from China National Knowledge Infrastructure (CNKI).
Studyselection Articles about “prevalence”, “gastric carcinoma”, “peptic ulcer”, “gastroesophageal reflux disease”, “functional dyspepsia”, “pathogenic mechanism”, “therapy”, “eradication rate”, “antibiotic resistance”, and “gene polymorphisms” were selected.
Results The decreased infection rates of H. pylori could also be linked to the changed disease spectrum, such as the decreased morbidity and recurrence rate of H. pylori-related peptic ulcer, and the increased morbidity of gastroesophageal reflux. Although different treatment regimens have been used for H. pylori infection, the H. pylori eradication rate declined gradually. Due to primary resistance to antibiotics, the gene polymorphism of host and infected strain, and the therapy regimes, H. pylori eradication became even more difficult.
Conclusions The prevalence of H. pylori infection had been decreasing, but the rate of eradication failure has dramatically risen in many countries due to resistance to antibiotic. H. pylori therapy in clinical practice is becoming progressively more difficult.
Helicobacter pylori(H. pylori) is one of the most common causes of bacterial infection in human beings. It is a gram-negative bacterium that inhabits the mucous layer of the gastric mucosa of the human stomach. It was first isolated and cultured from the antrum of patients with gastritis by Warren and Marshall in 1983. It can cause gastroduodenal disease and especially chronic gastritis and peptic ulcer. In recent years, theH. pyloriinfection rate had been decreasing and the antibiotic resistance rate had been increasing, which has resulted in changes in the disease spectrum and treatment regimens.
Epidemiological studies
The overall prevalence ofH. pyloriinfection was more than 50% among natural populations throughout the world, but there were great differences between various regions and nations.1The high prevalence ofH. pyloriinfection mainly focused on undeveloped countries and regions in Asia, Africa, and South America — such as Iran 64.2%, Portugal 66.2%, and Latin America 79.4%. The lack of basic sanitation, safe drinking water, basic healthcare, poor eating habits, and over-crowded living environment are responsible for the high prevalence ofH. pyloriinfection. However, a relatively low prevalence ofH. pyloriinfection exists in North America, Western Europe, and Australia — such as the Czech Republic 23.5%, Slovakia 30%, and Australia 15.5%.2-7
The prevalence ofH. pyloriinfection had been decreasing overall in recent years. However, high incidences ofH.pyloriinfection have now been reported in some countries. The incidence was significantly reduced to 23.5% by 2011, compared to 10 years ago (in 2001, 41.7%) in the relatively low-prevalence regions in Czech Republic.5The populations with low levels of education and ages older than 55 years were commonly associated with the high prevalence ofH. pyloriinfection. In Belgium, the incidence decreased remarkably over the past two decades (1988 to 2007).8The incidence fell from 36.2% to 15.2% for populations from Western Europe, while that fell from 71.7% to 40.0% for populations in North Africa. The incidence ofH. pyloriinfection was decreasing overall both in high- and low-prevalence regions. These phenomena were not only mainly related to the improvement of socioeconomic level and living conditions, but also were related to people’s deeper understanding of the disease. The population census and eradication therapy ofH. pyloriinfection were performed in regions with a high prevalence of gastric cancer.
Variations in incidence ofH. pyloriinfection and
associated diseases
In recent years,the disease spectrum changed along with the decreasing prevalence ofH. pyloriinfection. Meta-analysis showed that the evolutionary trends of birth cohort analysis for the incidence, hospitalization, and mortality of gastric ulcer, duodenal ulcer, gastric cancer, colon cancer, and rectal cancer were similar to that forH. pyloriinfection throughout the entire 20th century. However, the trend of gastroesophageal reflux disease (GERD) and esophageal adenocarcinoma was opposite to that. The temporal variations ofH. pyloriinfection have affected the occurrence of gastroenterology’s most common disorders.9
The data in the Third Hospital of Peking University10showed a gradually decreased detection rate ofH. pyloriinfection and peptic ulcer, while revealing an increased detection rate of reflux esophagitis annually. In 1996, the detection rates of duodenal ulcer, gastric ulcer, and reflux esophagitis were 15.91%, 3.62%, and 3.53%, respectively. In 2005, the detection rates were 8.30%, 2.71%, and 6.06%, respectively. In 1996, the detection rates ofH. pyloriinfection reached the peak, with 48.77%. In 2005, the rates reached the bottom, with 33.61%.H. pyloriinfection was a major cause of chronic gastritis and peptic ulcer. This conclusion has been confirmed by evidence-based medicine.11The studies found that 90% and 70% of cases of duodenal ulcer and gastric ulcer were attributed toH. pyloriinfection. The recurrence rate of ulcer declined from 60%-100% to 3%-10% afterH. pyloriinfection eradication. The refractory ulcer could be healed. With the reduced prevalence ofH. pyloriinfection, the incidence rate of peptic ulcer also decreased. However, the morbidity of drug-related peptic ulcer increased because of the higher incidence rate of cardiovascular disease and the augmented application of non-steroidal anti-inflammatory drugs. Furthermore, bleeding and morbidity rates increased significantly in peptic ulcer patients withH. pylori-negative infection.12
The relationship betweenH. pyloriinfection and the risk of developing GERD was controversial. Clinical epidemiological data indicated there was some negative correlation between the incidence ofH. pyloriinfection and GERD. However, the essence of the relationship was not clear. The studies also showed that the reflux symptoms and quality of life were improved in GERD patients one year afterH. pylorieradication therapy.13
It was unclear whetherH. pyloriinfection was the cause of non-ulcer dyspepsia. Data from two Randomized controlled trial (RCT) studies14,15showed no relationship between the eradication ofH. pyloriand the symptoms of functional dyspepsia (FD). However, another RCT study16considered that the dyspepsia was not improved obviously in 13% of participants in the treatment group, compared to 18.4% of participants in the placebo group seven years after the eradication ofH. pylori. The difference was statistically significant (odds ratio (OR)0.69, 95%CI: 0.51–0.88). Therefore, eradication ofH. pyloriinfection provided cumulative long-term benefit for dyspepsia patients.
The association betweenH. pyloriinfection and gastric cancer was summarized as follows:17-24(1) TheH. pyloriinfection in Mongolian gerbils induced the incidence of gastric cancer; (2) There was a significant correlation between the incidences ofH. pyloriinfection and the risk of gastric cancer in epidemiological studied.23In East Asia, with high prevalence ofH. pyloriinfection, the age-standardised incidence rate (ASR) of gastric cancer was 30, while the ASR in Latin America was 11.7. In regions with low prevalence ofH. pyloriinfection, the ASR was relatively low: 6.5 in Western Europe, 4.2 in North America. However, there were varying conclusions from other studies.24In North Africa and South Asia, with high prevalence ofH. pyloriinfection, the incidence rate of gastric cancer was low. The ASR was 4.2 and 5.3, known as the “African enigmas” and “Asian enigmas.” This might be associated with the population differences, including the pathogenicH. pyloristrains, the genetic background of populations, nutritional factors, and the inflammation reaction type ofH. pyloriinfection; (3) Eradication ofH. pyloriinfection might delay the progressive aggravation of gastric atrophy and intestinal metaplasia. Further study of whether it could reverse these two diseases was needed; (4) Eradication ofH. pyloriinfection could reduce the recurrence rate of early gastric cancer and metachronous carcinoma; (5) There was a closer relationship between theH. pyloriinfection carrying out some virulence genes and gastric cancer.
pathogenic mechanism
H. pyloriinfection could induce the chronic inflammation of gastric mucosa, but only a portion of the infected patients developed peptic ulcer or gastric cancer. The prognosis of infected patients might be associated with the virulence ofH. pyloristrain, host, environment, and dietary factors. Due to the genetic heterogeneity of theH. pylorigenome, the bacterial virulence factors might play an important role in determining the outcome ofH. pyloriinfection, such as CagA/cagPAI, VacA, iceA, and Duodenal ulcer-promoting gene (dupA), etc.25-30H. pylorivirulence factors and host genetic polymorphisms were considered to affect the incidence ofH. pylori-related disease of some specific ontogeny. However, the incidence of any disease was not influenced by one or several factors. It was the result of a series of cascades caused by multiple pathogenic factors and host factors. There was no relevant evidence indicating it was meaningful for the diagnosis and treatment of individual patients based on the detection ofH. pylorivirulence factors.
Therapy
Eradication programs and eradication rate ofH. pyloriinfection
Currently,H. pylorieradication therapy focused on several main points, as follows: Triple therapy was the preferred option in the absence of bismuth in low-incidence areas of clarithromycin resistance; the quadruple therapy based on bismuth had the highest titer; the individualised treatment was performed according to the antibiotic resistance; and the treatment lasted for 10 to 14 days. The treatment programs for the implementation ofH. pylorieradication therapy should be based on patient compliance, antibiotic medication history, and local antibiotic resistance. The common treatment programs included triple therapy, quadruple therapy (containing bismuth), sequential therapy, concomitant therapy (referred asprotonpumpinhibitor(PPI) and amoxicillin, clarithromycin and metronidazole, 10–14 days) and individual treatment. Adjuvant therapy might be helpful forH. pylorieradication. Probiotics has been suggested as a useful adjuvant therapy, but the levels of evidence and recommended levels are very low.22
The eradication rate of traditional triple therapy has been more than 90% in the past few decades. However, the eradication rates of triple therapy have dropped significantly, about 68% to 90.2% due to the increased antibiotic resistance worldwide, especially resistance to clarithromycin.31-34In 1996, the eradication rate of triple therapy was 88.9% in China.18In 2012, the rate reported in the literature was 73.5%.35In the low-prevalence regions of clarithromycin resistance, the eradication rates did not change to any significant degree. In Singapore, the eradication rate of PAC triple therapy (Pantoprazole, Amoxicillin, Clarithromycin) dropped from 90.2% in 2005 to 88.7% in 2010. There was no significant decline.31In the high-prevalence regions of clarithromycin resistance, the use of alternative metronidazole for clarithromycin also achieved better eradication rates. In Tokyo, the eradication rate decreased from 97.7% in 2007 to 91.8% in 2011.36The difference was not statistically significant. The latest MaastrichtIVproposed a consensus that the patients should abandon PPI-clarithromycin-containing triple therapy without prior susceptibility testing in the regions with clarithromycin resistance rates more than 15% to 20%.22If patients were sensitive to clarithromycin, this program could be used as the first-line therapy.
The efficiency of bismuth-based quadruple therapy reached 76% for patients who failed in first-line therapy.37TheORfor eradication ofH. pyloriwith sequential therapy compared with triple therapy was 2.99 (95%CI, 2.47-3.62). In patients with clarithromycin resistance, theORwas 10.21 (95%CI, 3.01-34.58).38The meta-analysis of 40 RCT studies showed that39the eradication rate of triple therapy was 68.4%-84.7%; the rate for the bismuth-containing quadruple therapy regimen lasting 10-14 days was 78.8%-90.1%; the rate for the non-bismuth-containing quadruple therapy regimen lasting 10-14 days was 74.9%-87%; and the eradication rate of sequential therapy was 82.1%-86.4%. The overall eradication rate of sequential therapy in patients harboring strains resistant to clarithromycin was 72.8%. The overall eradication rate in patients harbouring strains resistant to metronidazole was 86.4%. The overall eradication rate of sequential therapyin patients harboring strains resistant to both clarithromycin and metronidazole was just 37%. In patients harboring strains resistant to clarithromycin, sequential therapy achieved a significantly higher eradication rate. Its main disadvantage was the poor patient compliance resulting from complicated usage, and it was not suitable for patients harboring strains resistant to both clarithromycin and metronidazole.
Most studies showed that concomitant therapy was a good choice for the high-prevalence regions of clarithromycin resistance in the case of non-bismuth-containing therapy. But the following treatment would be a challenge if this program failed to eradicateH. pyloriinfection due to the use of three antibiotics. The eradication rate of concomitant therapy lasting seven days reached more than 90%.40,41A recent prospective RCT study showed that there was no significant difference in theH. pylorieradication rate and similar patients’ compliances between concomitant therapy (91%) and sequential therapy (86%).42
In patients with failed first-line and second-line therapy, the therapy regimens should be selected according to the individual sensitivity to antibiotics. The bacterial culture and drug susceptibility testing was a reasonable approach becauseH. pyloriinfection was latent. The limitation of susceptibility testing was based on the fact that thein vivoresistance could not be accurately reflected as inin vitrodrug trials, particularly for metronidazole.
Factors affecting the eradication rate
Antibiotic resistance
Because antibiotics were widely used and even abused in different regions and countries, the rates of antibiotic resistance have increased remarkably. Antibiotic resistance was one reason for the failure ofH. pylorieradication in many countries. Meta-analysis showed that 5.5%-84.9% of the strains were resistant to clarithromycin, 19.0%-65.5% were resistant to metronidazole, and 0.9%-37.1% were resistant to amoxicillin in 2011 and 2012.43-46The resistance rate differed among various countries and regions, and it had generally increased worldwide during recent years (Table 1). The resistance was more serious in developing countries than in developed Western countries.47,48
The primaryH. pylorieradication therapy program was very important. If the first treatment failed, a series of problems such as antibiotic resistance would occur and make the subsequent treatment troublesome. In Germany, from 2005 to 2012, the primary, secondary, and tertiary resistances to clarithromycin were 7.5%, 63.2%, and 75.4%, respectively. Primary, secondary, and tertiary resistances to levofloxacin were 11.7%, 17.6%, and 36.4%, and resistances to metronidazole were 32.7%, 63.2%, and 80.1%, respectively.54In Germany, the researchers observed a stable, but constantly increasing, resistance rate to antibiotics commonly used for the treatment ofH. pyloriinfection. The primary clarithromycin resistance rate rose from 2.2% up to 7.5%, and from 26.2% up to 32.7% for metronidazole (1995 to 2000, compared with 2005 to 2012).55
Host gene polymorphisms
Intragastric pH influenced theH. pylorieradication rate. Most antibiotics were effective in the condition of high intragastric pH. PPI was mainly metabolized by cytochrome P4502C19 (CYP2C19). According to CYP2C19 polymorphisms, patients could be divided into extensive metabolizers, intermediate metabolizers, and poor metabolizers. For extensive metabolizers, PPI was metabolized fast with low effective blood concentration, short maintaining peak time, and poor acid-suppressing effect. The efficacy of antibiotics was affected. Thereby, the extensive metabolizer phenotype of CYP2C19 was one of the reasons causingH. pylorieradication failure.
The distribution of CYP2C19 in different races was significantly different.56The percentage of poor metabolic genotypes was about 3% to 5% for Caucasian and African American, and 12% for Asians, of which 15% were Chinese and 19%-23% were Japanese. Meta-analysis showed that triple omeprazole and lansoprazole therapies achieved higherH. pylorieradication rates in the poor metabolizers than in extensive metabolizers. Rabeprazole therapies had no significant effect onH. pylorieradication rates between poor metabolizers and extensive metabolizers.57Therefore, after the failure ofH. pylorieradication, the CYP2C19 polymorphism could be detected to choose the drugs less affected by the CYP2C19 gene polymorphism, such as esomeprazole and rabeprazole, and improved the eradication rates.
Increased PPI dose could significantly improve theH. pylorieradication rate. High-dose PPI not only stabilized the high pH condition to exert an effective antibacterial efficiency, but also reduced the metabolism of PPI dependent on CYP2C19 enzyme. Meta-analysis indicated that theH. pylorieradication rate was increased by 6%-10%, or even higher if esomeprazole was administrated at 40 mg twice daily.58
Therapy duration
The appropriate duration of therapy reduced the phenotypic resistance ofH. pyloriand increased theH. pylorieradication rate. A study showed an eradication rate of 68.8% by standard triple therapy for seven days, and 71.76% for 10 days, in Spain.33Meta-analysis showed that the eradication rate reported for the triple therapy lasting seven days was 71.5%, 75.3% for ten days, and 81.3% for 14 days. The eradication rate for therapy lasting 14 days was significantly higher than for seven days and 10 days.39The difference was statistically significant, while there was no significant difference between seven days and 10 days. However, the eradication rates of sequential therapy lasting 10 and 14 days were 87.6% and 89.7%, respectively. The difference was not statistically significant. The study showed that the eradication rates for therapies lasting 7, 10, and 14 days were 74.1%, 78.8%, and 89.5%, respectively. The eradication rate lasting 14 days was higher than the 10-day group and seven-day group (P<0.01). The multivariate analysis showed that therapy time has a significant effect on eradication rates (P<0.05).35MaastrichtIVproposed that if a standard triple therapy regimen was extended from 7 to 10 and 14 days, the eradication rate increased by 5%.22
Conclusions
H. Pyloriinfection has been a worldwide health, medical, and economics problem as a chronic bacterial infection.H. pyloriinfection is related to various gastric diseases. The pathogenic mechanism has not been studied clearly. However, the bacterial virulence factor has not yet been found to assist the diagnosis and treatment of individual patients in clinics. Currently, the eradication rate of proton pump inhibitors combined with antibiotics is about 80%, but the adverse drug effects, reduced patient compliance, higher treatment costs, the growing number of drug-resistant strains, and increasing antibiotic resistance worldwide has occurred. Therefore, researchers needed to explore further methods and drugs to treatH. pyloriinfection.
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(Received October 23, 2013)
Edited by Ji Yuanyuan
Table 1.Changes of antibiotic resistance in recent years
Countries and regions Start and end year Amoxicillin (%) Clarithromycin (%) Metronidazole (%) Levofloxacin (%)
Gyeonggi, Korea49 2003–2012 7.1-18.5 22.9–37.0 - 5.7-34.6
Seoul, Korea50 2009–2012 5.6-2.1 7.0-16.0 45.1-6.4 26.8-22.3
Lithuania51 1998–2008 - 1.1-3.3 24.7-35.6 -
Beijing, China52 2000–2009 - 14.8-65.4 38.9-78.8
Japan53 1996–2004 1.8-29.0 - - -
  1. grants from National “Twelfth Five-Year” Plan for Science & Technology support program plan (No. 2012BAI06B00).