Management of Antibiotic-Resistant Helicobacter pylori Infection: Perspectives from Vietnam

Abstract

Antibiotic resistance is the most important factor leading to the failure of eradication regimens. This review focuses on the prevalence of Helicobacter pylori primary and secondary resistance to clarithromycin, metronidazole, amoxicillin, levofloxacin, tetracycline, and multidrug in Vietnam. We searched the PubMed, EMBASE, Vietnamese National Knowledge Infrastructure, and Vietnamese Biomedical databases from January 2000 to December 2016. The search terms included the following: H. pylori infection, antibiotic (including clarithromycin, metronidazole, amoxicillin, levofloxacin, tetracycline, and multidrug) resistance in Vietnam. The data were summarized in an extraction table and analyzed manually. Finally, Excel 2007 software was used to create charts. Ten studies (three studies in English and seven in Vietnamese) were included in this review. A total of 308, 412, 523, 408, 399, and 268 H. pylori strains were included in this review to evaluate the prevalence of H. pylori primary resistance to amoxicillin, clarithromycin, metronidazole, levofloxacin, tetracycline, and multidrug resistance, respectively. Overall, the primary resistance rates of amoxicillin, clarithromycin, metronidazole, levofloxacin, tetracycline, and multidrug resistance were 15.0%, 34.1%, 69.4%, 27.9%, 17.9% and 48.8%, respectively. Secondary resistance rates of amoxicillin, clarithromycin, metronidazole, levofloxacin, tetracycline, and multidrug resistance were 9.5%, 74.9%, 61.5%, 45.7%, 23.5% and 62.3%, respectively. In Vietnam, primary and secondary resistance to H. pylori is increasing over time and affects the effectiveness of H. pylori eradication.

INTRODUCTION

In 1983, Marshall and Warren¹ discovered Helicobacter pylori–a gram-negative bacillus that infects the human stomach mucosa. Further studies confirmed that H. pylori is the main cause of chronic gastritis, peptic ulcer disease, gastric marginal zone/mucosa-associated lymphoid tissue (MALT) lymphoma and gastric carcinoma.^2–7 Recently, it has been suggested that H. pylori may be associated with extraintestinal diseases, including immune thrombocytopenic purpura, refractory iron deficiency anemia and vitamin B₁₂ deficiency.^8,9 Globally H. pylori has been classified as a class I carcinogen and the major cause of gastric cancer.¹⁰

In Vietnam, frequency of H. pylori infection is rather popular and similar to that in the other developing countries. A large-scale study showed that frequency of H. pylori infection made up over 70% in adults and lightly reduced in children.^11–14 An investigation study in a hospital indicated that frequency of H. pylori infection was 59.9% to 69.9% for chronic gastritis; 77.8% for gastric ulcer; 85% to 95% for duodenal ulcer and 85.3% to 93.6% for gastroduodenal ulcer.^14–16

Generally, H. pylori eradication is indicated in cases of peptic ulcer including active, non-active and complicated, gastric MALT lymphoma, and to some extent, chronic gastritis and functional dyspepsia. Eradication of H. pylori not only heals peptic ulcers, but also prevents their recurrence and reduces the risk of development of gastric cancer.^17–21 In addition, diseases related to H. pylori such as MALT lymphoma, gastric atrophy and intestinal dysplasia are also recoverable after antibiotic treatment.^22,23

Triple therapy regimens including one proton pump inhibitor (PPI) and two antimicrobial agents such as amoxicillin (A), clarithromycin (C), metronidazole (M), levofloxacin (L), and tetracycline (Te) have been widely used to eradicate this bacterium. Although rate of successful eradication treatment depends on many factors such as smoking and patients’ compliance, antibiotic resistance is an important factor reducing treatment efficiency.^24,25 Rate of the antibiotic resistance is higher in the developing countries than in the developed countries.^26,27 In addition, the rate of antibiotic resistance often correlates with the amount of antibiotics consumed in the population.^3,28–30 In Vietnam, based on International Consensus, regimens of using two antibiotic drugs: clarithromycin and amoxicillin, or clarithromycin and metronidazole, are standard regimen to eradicate H. pylori.^20,31,32 In Vietnam, in early 1990s, rate of H. pylori eradication exceeded 90%. However, recent statistics indicate that H. pylori eradication rate has decreased to 60%–70%. The most important cause for the reduced success of standard triple therapy is the increasing rate of H. pylori clarithromycin/metronidazole/levofloxacin resistance.^33–35 In this review, we provide the following information: (1) frequency of H. pylori infection in Vietnam; (2) rate of H. pylori infection in chronic gastritis, gastric ulcer and gastric cancer in Vietnam; (3) efficiency of H. pylori eradication regimen in Vietnam; (4) antibiotic resistance rate of H. pylori in Vietnam; (5) the cause of H. pylori resistance in Vietnam; or (6) perspectives from Vietnam.

The data was summarized in extraction table and analyzed manually. Finally, Excel 2007 software (Microsoft, Redmond, WA, USA) was used to draw charts.

1. Prevalence and risk factors of H. pylori infection in Vietnam

There is a difference in rate of H. pylori infection among the Asian countries and even in a country.³⁶ The rate of H. pylori infection depends on socio-economic and environmental conditions. Frequency of H. pylori infection in the developing countries is often higher than that in the developed countries. In developing countries such as India and Saudi Arabia and African countries, the infection rate is high and approximately 80% of the population infected with H. pylori by 20 years old.³⁷ In contrast, the infection rate is reported to be as low as 10% to 20% in developed countries, and the infection rate increases at a rate of approximately 1% per year.³⁸ In Japan, the rate of H. pylori infection in children under the age of 10 is very low (approximately 5%) and the rate of H. pylori infection gradually increases by ages.³⁹

Vietnam is in the center of Southeast Asia Region and in the East of the Indochinese Peninsula and borders Chinese to the North, Laos and Cambodia to the West and the South China Sea and Pacific Sea to the Southeast. Vietnam has its population of about 94 million people and 54 ethnic groups, including over 80% of Kinh group. Vietnam divided into three different areas: Northern Vietnam (25 provinces), Central Vietnam (19 provinces), and Southern Vietnam (19 provinces). There are three main cities: Hanoi, Hue, and Ho Chi Minh City. Fig. 1 shows the map of Vietnam, with three different regions (north, central, and south), with three major cities in Vietnam (Hanoi, Hue, and Ho Chi Minh City).

Fig. 1.

Map of Vietnam with three different regions: North, Central, and South. Note: North Vietnam includes northwestern, northeast and Red River Delta areas. Central Vietnam includes north central coast, south central coast and central highlands. South Vietnam includes southeastern and Mekong River Delta areas. Reprinted with the permission of Nations Online Project.

Vietnam does not have a national survey of H. pylori infection epidemiology. The study only focused on some areas in major cities, or delta. These studies also focus only on Kinh people. Before 2010, there was no study on the epidemiology of H. pylori in the ethnic group

In 2005, Hoang et al.¹¹ conducted epidemiologic investigation of H. pylori infection rate in the community, including children and adults, through serological test, in urban (Hanoi) and rural Vietnam (Hatay province). Study results indicated that the rate of H. pylori infection in community was 74.6%. The rate of H. pylori infection in Hanoi (78.8%) was higher than that in Hatay (69.2%). This difference was significant (p=0.0007). These study results showed that the rate of H. pylori infection in the community in Vietnam is very high, especially in the urban areas (Hanoi). They proved that the frequency of H. pylori infection has gradually increased by ages, particularly at the age of 30 and above. The rate of H. pylori infection at the age of 30, 52, 59 and 83 is 33.3%, 49.2%, 69.2%, and 78.3%, respectively.¹¹ The study shows that the prevalence of H. pylori infection is high in Vietnam and especially high in large urban, such as the city of Hanoi.

Prevalence of H. pylori infection is also high in children. A study of Nguyen et al.¹² on 284 children at 6 months and 15 years, through serological test showed that the rate of H. pylori infection in children was 34.0%. Study examined the relationship between H. pylori infection and a number of factors, including: sociodemographic characteristics, health status, environmental status, health status, and so on. Study concluded that person-to-person transmission and sociodemographic factors are factors associated with H. pylori infection

Besides the serological test, urine tests are conducted to investigate the rate of H. pylori infection in community, as well as applied for people with gastric diseases. Nguyen et al.¹⁵ found that Rapirun test had sensitivity, specificity and accuracy rate of 79.5%, 90.7%, and 84.5%, respectively. These results were similar to those of Quach et al.⁴⁰ upon testing and finding H. pylori in 200 patients by Rapirun Stick test to obtain sensitivity, specificity and accuracy rate of 84.7%, 89.9%, and 87%, respectively. However, these urine tests only helped investigation of H. pylori infection rate in community.

Recently, there have been some epidemiological investigation of H. pylori infection rates in ethnic, including adults and children.^41–44 In 2014, Binh et al.,⁴¹ investigated H. pylori infection rates (five different methods) on 494 volunteers. Research subjects are ethnic in two different areas: Lao Cai province (North Vietnam), Daklak Province (Central Vietnam). Results of the study indicate that the prevalence of H. pylori infection among ethnic minorities (adults) was 188 out of 494 (38.1%). There were significant differences in rates of H. pylori infection in Daklak and Lao Cai (51.0% vs 29.3%, p<0.001). There are many factors may contribute to H. pylori infection such as geographical location, ethnicities, dietary habit, etc. The results showed that subjects living in Daklak had a significantly higher risk of H. pylori infection than those in Lao Cai (crude odds ratio [OR], 2.52; 95% confidence interval [CI], 1.73 to 3.65). With respect to minor ethnic groups, E De (crude OR, 2.44; 95% CI, 1.64 to 3.62) was at significantly higher risk, whereas Tay (crude OR, 0.3095%; CI, 0.16 to 0.56) and Dao (crude OR, 0.37; 95% CI, 0.17 to 0.73) were at significantly lower risk of H. pylori acquisition.

Nguyen et al.⁴² was studied the epidemiology of H. pylori infection in Khmer children in Mekong Delta (South Vietnam). Research results showed that the prevalence of H. pylori infection among children of Khmer ethnicity is 32.1%. H. pylori infection in mothers, in first sibling and in two first siblings in particular were found as high-risk factors for H. pylori infection in children (OR, 1.98; 95% CI, 1.12 to 3.18; OR, 2.12; 95% CI, 1.2 to 4.12; OR, 4.39; 95% CI, 2.81 to 6.94; respectively).

According to the statistics of the Government of Vietnam (2009), the Tay is the second largest ethnic group in Vietnam after the majority Kinh ethnic. Tay people live mainly in the mountains of northern Vietnam. Nguyen et al.⁴³ showed that epidemiology of H. pylori infection in Tay children (Lang Son province-North Vietnam). Study concluded that intra-familial H. pylori transmission are factors associated with H. pylori infection. In 2017, Nguyen et al.⁴⁴ also investigated the epidemiology of H. pylori infection in Muong people. Muong is the thirst largest ethnic group in Vietnam after the majority Kinh and Tay ethnic group. The findings showed a familial clustering in these multi-generation familial structures and supported the hypothesis of person-to-person transmission in H. pylori infection.

Limitations of the study in Vietnam focused on the region and the number of volunteers has less.^41–44 However, the above studies show that family, race, geography, life-style and age are related to H. pylori infection in Vietnam.

Today, the economic conditions of Vietnam are going up, improve public sanitation, improve health care, could also be a factor in reducing the rate of H. pylori infection in the community. However, to demonstrate this matter, should have investigated the epidemiology of H. pylori infection nationwide.

In Korea, Lim et al.⁴⁵ has evaluated the time trend of seropositivity of H. pylori over the period of 13 years in an asymptomatic Korean population, and investigate associated risk factors. The overall seroprevalence of H. pylori infection was 54.4% (95% CI, 53.5% to 55.4%) in 2011 which is significantly decreased from 66.9% (95% CI, 65.4% to 68.6%) in 1998, and 59.6% (95% CI, 58.5 to 60.7%) in 2005 (p<0.001). Factors including elderly, male gender, low income, residence in a rural area and high cholesterol (≥240 mg/dL) (OR, 1.33; 95% CI, 1.14 to 1.54) are related to H. pylori infection.

PREVALENCE H. PYLORI INFECTION IN GASTRIC DISEASES IN VIETNAM

1. Prevalence H. pylori infection in patients with chronic gastritis

Chronic gastritis is rather popular among the gastric diseases. But the studies of the rate of H. pylori infection in patients with chronic gastritis focused on Kinh group. In 2003, Long et al.⁴⁶ collaborated with Fukui University (Japan) to determine the rate of H. pylori infection by three methods: urease test, histopathology and serological test (ELISA) in 104 patients with gastric cancer and 104 patients with chronic gastritis. Study results indicated that the rate of positive H. pylori infection on the tests: urease test, histopathology and serological test was 44.5%; 57.6% and 88.1%, respectively.

Thang⁴⁷ found that the rate of H. pylori infection in patients with chronic gastritis (n=235) was 75.9% (determined by histopathology and CLO test). Thinh⁴⁸ using four various methods: urease test, polymerase chain reaction (PCR), histopathology and culture showed that the rates of H. pylori infection were 58.1%, 58.1%, 56.3% and 57.0%, respectively. Dung⁴⁹ also obtained similar results, with the rate of 59.9%. Thus, these study results proved that the rate H. pylori infection in patients with chronic gastritis in Kinh group is rather high.

Recently, studies of the frequency of H. pylori infection in the ethnic groups of Vietnam have been conducted. Binh et al.⁴¹ conducted a study of the rate of H. pylori infection in the ethnic groups in Daklak (Central Highlands–Vietnam) and Lao Cai (North Vietnam). The author used four combined methods; including culture, histopathology-immunohistochemical, test urease and serological test. Study results pointed out that the rate of H. pylori infection was 188 out of 494 (38.1%), in which the rate of H. pylori infection in Lao Cai province (51.0%) significantly increased (crude OR, 2.52; 95% CI, 1.73 to 3.65) higher than that in Daklak province (29.3%).

2. Prevalence of H. pylori infection in patients with gastroduodenal ulcer in Vietnam

There are two main causes of gastric duodenal ulcer: using nonsteroidal anti-inflammatory drugs and H. pylori infection. Many studies of the rate of H. pylori infection in patients with gastric duodenal ulcer have been conducted.

A study of Long⁵⁰ on 300 patients with gastroduodenal ulcer pointed out that the rate of H. pylori infection was 91.7%. A study of Huong⁵¹ on patients with gastroduodenal ulcer in Hue National Hospital for 2 years (1998 to 1999), the rate of H. pylori infection was 72.6%, while the rate of H. pylori infection in patients with duodenal ulcer was 79.1%.

Nguyen et al.¹⁴ combined five different methods (urease test, histopathology, culture, serological test, and immunohistochemical) to determine that rate of H. pylori infection on 270 patients, including gastric ulcer (n=38), chronic gastritis (n=245), gastroesophageal reflux disease (n=9), and normal (n=25). Study results showed that the rate of H. pylori infection was 177 out of 270 (65.6%). There is no significant difference in the rate of H. pylori infection between male and female patients (66.0% and 65.0%) as well as between Hanoi and Ho Chi Minh City (66.4% and 64.7%).

3. Prevalence of H. pylori infection in patients with gastric cancer

Globally H. pylori has been classified as a class I carcinogen and the major cause of gastric cancer.¹⁰ Many studies focused on the relation between the gastric cancer and the rate of H. pylori infection, virulence factors of H. pylori (cagA, vacA, etc.). Hop and Tho⁵² studied on 205 patients with gastric cancer and the rate of H. pylori infection was 136 out of 250 (66.3%). Long et al.⁴⁶ found that the rate of positive H. pylori infection in patients with gastric cancer on the tests (n=104): Urease test, histopathology and serological test (ELISA) was 55.1%, 71.1%, and 90.6%, respectively. Binh et al.⁴¹ found that the rate of positive H. pylori infection by four methods (culture, histopathology, urease test, and serological test) on 282 in patients with gastric cancer was 224 out of 282 (79.4%). There is no difference in the rate of H. pylori infection in patients with gastric cancer between in Hanoi (77.3%) and in Ho Chi Minh City (80.5%).

These results showed that the frequency of H. pylori infection increased not only in community but also in gastric diseases (chronic gastritis, gastric ulcer, duodenal ulcer, and gastric cancer). Further studies of virulence factor of H. pylori (cagA and vacA) indicated close relation between H. pylori infection and the gastric diseases in Vietnam.^14,15,53 Therefore, H. pylori eradication is necessary, especially in patients with chronic gastritis and gastric duodenal ulcer.

EFFICIENCY OF H. PYLORI ERADICATION REGIMEN IN VIETNAM

1. Efficiency of H. pylori eradication by first-line therapy

Triple therapy has been early and widely used in three regions of Vietnam (North, Central, and South Vietnam). In the decade: 1990 to 2000, when there had not been the antibiotic resistance, the triple therapy had been widely applied in clinical treatment in Vietnam. The triple therapy includes a proton pump inhibitors (PPI) and two antibiotics. PPIs having been used in Vietnam consist of omeprazole, lansoprazole, pantoprazole, rabeprazole and esomeprazole. There are three antibiotics commonly used in legacy triple therapies including clarithromycin (CLR), amoxicillin (AMX), metronidazole (MNZ).

The appropriate regimen is to achieve the following criteria:⁵⁴ (1) Efficacy of eradication of H. pylori should be >90% as per protocol (PP) and >80% according to the intent to treat (ITT); (2) Low side effects, patients’ easy to accept and reasonable prices, etc.

Underlying methods in the published papers and analyzed data from different hospitals in Vietnam were selected for this review. All most patients were undergone upper gastrointestinal endoscopy and tested for H. pylori (before and after treatment for 30 days).

Diagnosis of H. pylori infection by histopathology: two gastric biopsy specimens, one from the antrum and one from the corpus, were fixed in 10% formalin in separate containers and were sent to the pathology laboratory. Samples were embedded in paraffin wax, cut at 5 μm thickness, and stained with modified Giemsa and hematoxylin and eosin. Histological evaluation of the samples for H. pylori was performed according to the modified Sydney system.

Rapid urease test (RUT) is the most useful invasive test for the diagnosis of H. pylori infection because it is inexpensive, rapid, easy to perform and shows high sensitivity. Several commercial urease tests including gel-based tests (CLO test, HpFast), paper-based tests (PyloriTek, ProntoDry) and liquid-based tests (UFT300, EndoscHp) are available now.

Recently, we also use the breath test to detect H. pylori. However, we only use the ¹⁴C-urease breath test (¹⁴C-UBT).⁵⁵

Before 2010, techniques for the detection of H. pylori infection as UBT, cultures are not applied much (due to lack of equipment and lack of funds). Thus, most studies use RUT and/or histopathology to evaluate the efficacy of H. pylori eradication. Two studies have used RUT to detect H. pylori infection.^56,57 One study⁵⁵ used a ¹⁴C-UBT.

Table 1 presents efficiency of triple therapy in treatment for patients with gastroduodenal ulcer due to H. pylori infection. The studies are divided into three regions: North Vietnam (seven studies),^56–62 Central Vietnam (two studies)^63,64 and South Vietnam (three studies).^55,65,66 Results showed the rate of H. pylori eradication in North Vietnam (67.9% to 98.1%) and in Central Vietnam (84.7% to 90.0%), higher than that in South Vietnam (62.8% to 88.2%). Maximum efficiency of H. pylori eradication in 2002 was 98.1%⁵⁹ and minimum efficiency of H. pylori eradication in 2011 was 62.8%.⁵⁷

Table 1.

Results of Helicobacter pylori Eradication in Triple First-Line Therapy in Vietnam

Author	Local	Year	Regimens	Patient (n)	Time (day)	Method	H. pylori eradication rate
Mao et al.58	North	2000	OAC	54	10	PyloriTek test & histology	91.0
			R*AC	45	10	PyloriTek test & histology	96.0
Hai59	North	2002	EAC	53	10	CLO test & histology	98.1
Vinh et al.60	North	2003	OAC	59	7	PyloriTek test & histology	91.7
			OAM	57	7	PyloriTek test & histology	73.9
			OMC	58	7	PyloriTek test & histology	82.2
Duat et al.56	North	2007	PAC	106	7	CLO test	95.8
Tiep et al.61	North	2008	RAC	36	7	CLO test & histology	91.6
Thang57	North	2010	EAC	30	7	CLO test	90.0
			EAC	30	7	CLO test	93.3
Vinh62	North	2014	EAC	162	10	HpFast test & histology	67.9
Huong and Thang63	Central	2007	EAC	77	7	CLO test & histology	90.0
Nho et al.64	Central	2011	EAC	72	14	CLO test & histology	84.7
Ngoi65	South	2009	OAC	35	14	CLO test & histology	68.5
			OAL	35	14	CLO test & histology	88.2
Trung et al.55	South	2009	EAC	43	7	CLO test & UBT	68.3
			EAL	38	10	CLO test & UBT	70.2
Hoang66	South	2011	PAC	80	10	CLO test & histology	62.8

A, amoxicillin; C, clarithromycin; E, esomeprazole; M, metronidazole; L, levofloxacin; R, rabeprazole; P, pantoprazole; O, omeprazole; R*, ranitidine bismuth citrate; CLO test, campylobacter-like organism test; UBT, urease breath test.

A common feature for three regions indicated that the rate of H. pylori eradication has trended to decrease by time, especially in the South Vietnam: 88.2% in 2009⁶⁵ and 62.8% in 2011.⁶⁶ Similarly, the rate of H. pylori eradication in the North Vietnam was very high 98.1% in 2002⁵⁹ but reduced: 67.9% in 2014.⁶²

In the South (Vietnam), due to increased drug resistance, a number of studies have used levofloxacin in first-line regimens (triple therapy) to treat H. pylori eradication.^55,65 However, the results were opposite. Trung et al.⁵⁵ found that no difference in the efficacy of H. pylori eradication in EAL regimen (70.2%) versus EAC regimen (68.3%). On contrary, Ngoi⁶⁵ showed efficiency of H. pylori eradication in OAL therapy (88.2%), significantly higher than that in OAC therapy (68.5%). Vinh⁶² indicated that the rate of H. pylori eradication was only 68%; the rate of clarithromycin resistance was 71 out of 175 (40.6%) and the rate of amoxicillin resistance was 43 out of 175 (24.6%).

In Vietnam, for 11 years (2000 to 2011), the rate of H. pylori eradication by first line therapy (triple therapy) was significantly reduced: 91.0% in 2000⁵⁸ to 62.8% in 2011.⁶⁶ Hence, it is required to change treatment strategy using sequential therapy, or concomitant therapy, or bismuth-containing quadruple therapy, or rescue therapy. Based on the world’s recommendations and statistic figures of the antibiotic resistance to H. pylori, on June 2012, in Ho Chi Minh City, Vietnam Association of Gastroenterology⁶⁷ concluded a consensus of diagnosis and treatment of H. pylori infection.

2. Eradication of H. pylori by second-line regimen

The second indication of H. pylori eradication is recommended after the first treatment is unsuccessful.^68,69 Results of the second H. pylori eradication treatment often depends on many factors, in which the antibiotic resistance to H. pylori has been increasing, especially clarithromycin/metronidazole/levofloxacin resistance. The Maastricht IV consensus recommended bismuth containing quadruple therapy or levofloxacin containing triple therapy as second-line treatment options.⁸

In Vietnam, from 2009 to 2016, five studies^70–74 used second-line therapy for H. pylori eradication (Table 2). Trung et al.⁷⁰ found that H. pylori eradication of the quadruple therapy (EBMT) (95.7%) was more efficient than the triple therapy (EAL) with levofloxacin (58.8%) (p=0.013). This study recommends that levofloxacin should not be used in rescue regimens in Southern Vietnam.⁷⁰

Table 2.

Results of Helicobacter pylori Eradication by the Second Treatment Regimen in Vietnam

Author	Local	Year	Regimens	Patient (n)	Time (day)	Methods	H. pylori eradication rate
Trung et al.70	South	2008	EAL	19	10	CLO test & UBT	58.8
			EBMT	26	14	CLO test & UBT	95.7
Vinh71	North	2011	EAC	31	10	PyloriTek test & histology	80.7
			EBMT	45	14	PyloriTek test & histology	86.7
Hue et al.72	South	2016	EBMT	166	10	E-test & histology	89.3
Di and Thang73	Central	2012	EAL	101	10	CLO test & histology	83.2
Thang and Anh74	Central	2015	RLTi	59	7	CLO test & histology	86.3

A, amoxicillin; B, bismuth; C, clarithromycin; E, esomeprazole; M, metronidazole; L, levofloxacin; R, rabeprazole; T, tetracycline; Ti, tinidazole; UBT, urea breath test; CLO test, campylobacter-like organism test.

Vinh⁷¹ found that the rate of H. pylori eradication was higher with EBMT (96.7%) than with EAC (80.7%) (p<0.05). However, EBMT therapy had more side-effects (46.7%) than EAC therapy (12.3%). Hue et al.⁷² found that the efficacy of eradication of H. pylori by EBMT was 89.3%. However, in this study, the number of patients with moderate, severe and severe adverse events was 19.88%, 0.60% and 1.81%, respectively. Other two studies using the triple therapy with levofloxacin had the rate of H. pylori eradication of over 80%.^73,74 These results indicate that the therapeutic effect of levofloxacin in the rescue regimen is low and is associated with H. pylori resistance.

These results show that primary and secondary antibiotic resistance of H. pylori in Vietnam has increased over time, especially for clarithromycin and metronidazole. However, limitations in our study that the number of studies is small, intermittent and use classic methods (RUT, endoscopy and histology) to detect H. pylori. Therefore, there should be many more studies, in many different centers and longer duration.

ANTIBIOTIC RESISTANCE OF H. PYLORI IN VIETNAM

1. Prevalence of primary antibiotic resistance of H. pylori from 2001 to 2016

There are many factors that affect efficiency of H. pylori eradication therapies such as patient’s compliance, doses, quality of drugs, combined diseases, etc. Among those factors, the emergence of antibiotic-resistant H. pylori strains have been implicated as highest risk of treatment failure. The antibiotic resistance to H. pylori is divided into two types: primary antibiotic resistance and secondary antibiotic resistance.

There are two methods for detecting H. pylori resistance, including resistance to phenotypic resistance and genotype resistance. Phenotypic methods are applied in Vietnam since 2000. The methods include agar dilution method, disk dilution method and Epsilometer test. Method of detecting H. pylori genotype resistance has only been applied in recent years.

Table 3 presents the rate of primary antibiotic resistance to H. pylori in Vietnam from 2001 to 2016 period (16 years).^{16,33–35,75–80} Ten studies (three papers in English and seven papers in Vietnamese) were included in this review. A total of 308, 412, 523, 408, 399, and 268 H. pylori strains were included in this review to evaluate the prevalence of H. pylori primary resistance to amoxicillin, clarithromycin, metronidazole, levofloxacin, tetracycline, and multidrug resistance, respectively. Overall, the primary resistance rates of amoxicillin, clarithromycin, metronidazole, levofloxacin, tetracycline, and multidrug resistance were 15.0%, 34.1%, 69.4%, 27.9%, 17.9%, and 48.8%, respectively. Here, we also analyze in detail the rate of H. pylori resistance to the most commonly used antibiotics in H. pylori treatment in Vietnam. Fig. 2. shows the average rate of primary resistance of H. pylori with amoxicillin, clarithromycin, metronidazole, levofloxacin, and tetracycline in Vietnam during 16 years (from 2001 to 2016).

Table 3.

Rate of Primary Antibiotic Resistance of Helicobacter pylori in Vietnam (2001–2016)

Author/strains (n)	Year/local	Method	Primary antibiotics resistance (%)
			A	C	M	L	Te	Multidrug resistance*
Hoan75 (n=152)	2001/North	ADM	0	0	38.1		5.8
Vinh76 (n=178)	2003/North	E-test & ADM	18.1	21.6	54.3
Nhan and Mai77 (n=69)	2006/South	ADM	0	38.5	50.8		9.2
Thinh et al.78 (n=73)	2009/North	DDM	33.9	21.4	94.6		21.4
Nguyet and Hanh79 (n=98)	2010/North	DDM	35.5	26.7	95.5		17.8
Toan et al.80 (n=172)	2012/North	DDM	43.6	36.6	94.2		20.9	56.4
Binh et al.33 (n=103)	2013†	E-test	0	33.0	69.9	18.4	5.8	24.3
Dung et al.16 (n=220)	2015‡	ADM	7.7	43.6	83.6	33.2	10.9	58.2
Phan et al.34 (n=73)	2015/Central	E-test	0	34.2	75.3	35.6		50.7
Quek et al.35 (n=193)	2016/South	E-test	10.4	85.5	37.8	24.4
Mean			14.9	34.1	69.4	27.9	17.9	47.4

A, amoxicillin; C, clarithromycin; M, metronidazole; L, levofloxacin; Te, tetracycline; ADM, agar dilution method; E-test, Epsilometer test; DDM, disk diffusion method. E-test³³ (AB Biodisk, Solna, Sweden), E-test³⁴ (bioMerieux, Marcy I’Etoile, France), E-test³⁵ (bioMerieux).

^*Multidrug resistance: includes resistance to at least two antibiotics;

^†North Vietnam + South Vietnam;

^‡North Vietnam + Central Vietnam + South Vietnam.

Fig. 2.

Average rate of primary resistance with Helicobacter pylori in Vietnam from 2001 to 2016.

2. Prevalence of secondary antibiotic resistance of H. pylori from 2001 to 2016

Studies on secondary resistance of H. pylori in Vietnam have been less published. From 2014 to 2016, three studies have been published (two papers in Vietnamese and one paper in English).^34,81,82 These studies only in central and Southern Vietnam-where the rate of primary drug resistance tends to increase. Table 4 presents the rate of secondary antibiotic resistance to H. pylori in Vietnam trends in clarithromycin, levofloxacin and multiple drug resistance in Southern Vietnam are likely to increase over time. Minh and Hoang⁸¹ studied the rate of secondary resistance to H. pylori in 102 patients who failed treatment (at least one time). Research results showed that the secondary resistance rates of amoxicillin, clarithromycin, metronidazole, levofloxacin and tetracycline were 13.7%, 56.9%, 44.1%, 25.5%, and 23.5%, respectively. Hue⁸² showed that secondary rates of resistance to clarithromycin, levofloxacin and multidrug were 94.3%, 48.6%, and 45.7%, respectively.

Table 4.

Rate of Secondary Antibiotic Resistance of Helicobacter pylori in Vietnam (2014–2016)

Author/strains (n)	Year/local	Method	Primary antibiotics resistance (%)
			A	C	M	L	Te	Multidrug resistance*
Minh et al.81 (n=102)	2014/South	ADM	13.7	56.9	44.1	25.5	23.5	-
Phan et al.34 (n=19)	2015/Central	E-test	5.3	73.7	78.9	63.2	-	78.9
Hue82 (n=35)	2016/South	E-test	-	94.3	-	48.6	-	45.7†
Mean			9.5	74.9	61.5	45.7	23.5	62.3

A, amoxicillin; C, clarithromycin; M, metronidazole; L, levofloxacin; Te, tetracycline; ADM, agar dilution method; E-test, Epsilometer test.

^*Multidrug resistance: includes resistance to at least two antibiotics;

^†Clarithromycin+levofloxacin.

In Central Vietnam, the secondary resistance rates of clarithromycin and levofloxacin are also likely to increase. Phan et al.³⁴ showed that secondary rates of resistance to amoxicillin, clarithromycin, metronidazole, levofloxacin and multidrug were 5.3%, 73.7%, 78.9%, 63.2%, and 78.9%, respectively.

Overall, the secondary resistance rates of amoxicillin, clarithromycin, metronidazole, levofloxacin, tetracycline, and multidrug resistance were 9.5%, 74.9%, 61.5%, 45.7%, 23.5%, and 62.3%, respectively.

Today, antibiotic resistance of H. pylori has become more serious and affect the outcome of treatment. The prevalence of bacterial resistance varies in different geographic areas and appears to be increasing with time in many countries. The European multicenter study group included 2,204 patients from 2008 to 2009, spanning 18 European countries and demonstrated H. pylori resistance rates to clarithromycin, metronidazole and levofloxacin at 17.5%, 34.9%, and 14.1% respectively.⁸³

Recently, Kuo et al.⁸⁴ have reviewed the system and meta-analysis of primary antibiotic resistance to H. pylori and the efficacy of first-line regimens in the Asia-Pacific region. The overall mean prevalence of primary H. pylori resistance were 17% (95% CI, 15% to 18%) for clarithromycin, 44% (95% CI, 39% to 48%) for metronidazole, 18% (95% CI, 15% to 22%) for levofloxacin, 3% (95% CI, 2% to 5%) for amoxicillin, and 4% (95% CI, 2% to 5%) for tetracycline. Prevalence of resistance to clarithromycin and levofloxacin rose significantly over time during the period investigated, whereas resistance to other antibiotics remained stable. In Vietnam, the prevalence of primary resistance of H. pylori with clarithromycin and metronidazole was 34.0% and 72.0%, respectively, and it was ranked second (after Pakistan).⁸⁵

In Korea, Lee et al.⁸⁵ studied the prevalence of primary and secondary resistance of H. pylori in 347 patients during 2003 to 2012. The study results showed that the prevalence of primary resistance of H. pylori increases for amoxicillin (6.3% to 14.9%, p=0.051), clarithromycin (17.2% to 23.7%, p=0.323) and both of levofloxacin and moxifloxacin (4.7% to 28.1%, p=0.002). Secondary resistance rate significantly increased in metronidazole, levofloxacin and moxifloxacin.⁸⁵

3. Primary and secondary clarithromycin resistance of H. pylori in Vietnam

Because clarithromycin is the most potent antibiotic involved in the management of H. pylori infections, resistance to clarithromycin is important.^86,87 In European regions,⁸⁸ the lowest clarithromycin resistance was reported from Norway (5.9%), whilst the highest in Spain (32.01%) and Portugal (42.35%). European studies performed at the past 6 years intervals reported that H. pylori resistance decreased from 36.65% in 2009 to 24.38% in 2014. In Asian, mean overall prevalence of resistance to clarithromycin was 17% (95% CI, 15% to 18%), ranging from 0% in Bhutan and Myanmar to 34% in Vietnam and 37% in Pakistan.⁸⁴

In Vietnam, clarithromycin is the first line antibiotic selected in the triple therapy for H. pylori eradication treatment. Table 3 shows the proportion of primary resistance clarithromycin according to various studies.^{16,33–35,75–80} Rate of primary resistance to clarithromycin ranged from 21.4% to 85.5%. Therefore, clarithromycin resistance has increased, especially in the studies in the South Vietnam.³⁵ In the North Vietnam, clarithromycin resistance had trended to further increase from 18.5% in 2013 to 42.1% in 2015 (Table 5).¹⁶

Table 5.

Rate of Antibiotic Resistance of Helicobacter pylori in Hanoi and Ho Chi Minh City-Vietnam

Local	Antibiotic	Binh et al. (2013)33	Dung et al. (2015)16
Hanoi	Amoxicillin (A)	0	3.9
	Clarithromycin (C)	18.5	42.1
	Metronidazole (M)	70.3	89.5
	Levofloxacin (L)	18.5	21.1
	Tetracycline (Te)	7.4	11.8
Ho Chi Minh City	Amoxicillin (A)	0	6.9
	Clarithromycin (C)	49.0	39.2
	Metronidazole (M)	69.3	81.4
	Levofloxacin (L)	18.3	41.2
	Tetracycline (Te)	4.0	12.7

Data are presented as percentage.

The patients with the primary clarithromycin resistance will have risk of the secondary resistance. For the 2006 to 2008 period, a study in the South of Poland found that the primary clarithromycin resistance was 21% and the secondary resistance was 80%.⁸⁹ In Thailand, in 2009, there was a report on rate of the primary resistance after treatment of 78.7%, compared to the secondary resistance of 10.6%.⁹⁰

In Vietnam, in 2003, Vinh⁷⁶ found that the rate of clarithromycin resistance was 21.6% before treatment and 78.9% after treatment. Minh and Hoang⁸¹ found that the rate of clarithromycin resistance after 1, 2 and 3 treatments was incremental and 44.0%; 66.7% and 83.6%, respectively (Table 4). Phan et al.³⁴ indicated very high rate of the primary and secondary clarithromycin resistance: 34.2% and 73.7%, respectively (p<0.05). The rate of primary and secondary resistance of H. pylori to clarithromycin has increased, affecting the therapeutic effect. The Maastricht III guidelines on H. pylori infection management recommend substituting metronidazole for clarithromycin when resistance to this antibiotic exceeds 15% to 20%.²⁰

4. Primary and secondary amoxicillin resistance of H. pylori in Vietnam

Resistance to amoxicillin has been shown to be negligible (0 to <2%) in European countries, such as Germany and the Netherlands.⁹¹ In Asia, mean overall prevalence of resistance to amoxicillin was 3% (95% CI, 21% to 34%).⁸⁴

In Vietnam, amoxicillin is used in the triple therapy or the quadruple therapy for H. pylori eradication. The rate of the primary amoxicillin resistance varies in different times and studies: from 0% to 43.6% (Table 3).^33,77,80 The rate of the primary amoxicillin resistance in the North Vietnam has trended to further increase (18.1% to 43.6%)^76,78–80 than in the South Vietnam (0% to 10.4%) (Table 3).^{16,33–35,77}

Vinh⁷⁶ found that the rate of the secondary resistance of amoxicillin was 36.8%. Minh and Hoang⁸¹ found that the rate of the secondary amoxicillin resistance after 1, 2 and 3 treatments was 13.6%, 16.7%, and 0% (Table 4). Secondary resistance rates of amoxicillin in Southern Vietnam are lower than in the North Vietnam. Because of amoxicillin resistance rate is not high, so amoxicillin still used for H. pylori eradication in Vietnam.

5. Primary and secondary metronidazole resistance of H. pylori in Vietnam

Metronidazole in order to eradicate this bacterium, has been widely used in combination therapies such as metronidazole–based triple therapy, concomitant therapy and bismuth-containing quadruple therapy. Metronidazole resistance is the most common antibiotic resistance in H. pylori and overall metronidazole resistance found in 47.22% in descending order in Africa 75.02%, South America 52.85%, Asia 46.57%, Europe 31.19%, to 30.5% in North America.⁸⁸ In Asia, mean overall prevalence of resistance to metronidazole was 44% (95% CI, 39% to 48%) ranging from 10% in Japan to 84% in Bangladesh and 88% in Nepan.⁸⁴

In the 1990s, metronidazole was early used in H. pylori eradication regimen and used in the North Vietnam more than in the South Vietnam. Primary resistance rate of metronidazole from: 37.8%³⁵ to 95.5%.⁷⁷ The rate of the primary metronidazole resistance in the North Vietnam increased (38.1% to 95.5%)^75,79 higher than that in the South Vietnam (37.8% to 50.8%) (Table 3).^35,77 The rate of the primary metronidazole resistance has increased by time. In Hanoi, the rate of the primary metronidazole resistance increased from 70.3% in 2013 to 89.5% in 2015 (Table 5). In Ho Chi Minh City, the rate of the primary metronidazole resistance increased from 69.3% in 2013 to 81.4% in 2015 (Table 5).^16,33

Metronidazole is used frequently to treat not only H. pylori infection but also other infections such as intestinal parasites, periodontal, and gynecological diseases, which are common in developing countries, including Vietnam.²⁶ Because the drug has many side-effects, causing tiredness for the patients and high rate of resistance, metronidazole has not been used in the regimen of H. pylori eradication in Vietnam.⁶⁷

6. Primary and secondary tetracycline resistance of H. pylori in Vietnam

In the world, the rate of tetracycline resistance is low, especially in the developed countries.⁹⁰ In Asia and Africa, tetracycline and bismuth are used more than in Europe and the America.^84,88 The total rate of tetracycline resistance did not vary in South America and North America (the resistance was absent), whilst it was relatively high in Africa (50%). In Asia, the resistance was absent in Thailand, and very low in China (0.6%) and South Korea (0.01%). In contrast, increased values were found in India (53.8%), and Iran (11.7%). The prevalence of tetracycline resistance stays very low (less than 7.4%) in almost parts of the world except for Africa.⁸⁸ The comparison of data showed that tetracycline resistance was decreasing in the world, 26.85% in 2009 to 6.11% in 2014.⁸⁸

In Vietnam (see Table 5), the primary tetracycline resistance ranges 5.8% to 21.4% (Table 3). Minh and Hoang⁸¹ found that the rate of the secondary tetracycline resistance after 1, 2, and 3 treatments (Table 4) was 19.7%, 30.0%, and 33.3%, respectively. So far, the research and use of tetracycline for the eradication of H. pylori in Vietnam is very limited.

7. Primary and secondary levofloxacin resistance of H. pylori in Vietnam

Many studies have examined levofloxacin-PPI as a first-line therapy for eradication of H. pylori infection.^92,93 However, the eradication rates achieved with first-line levofloxacin-based treatments are not uniform. Some reports show the improved efficacy with levofloxacin-based regimens in comparison to standard first-line therapy, whereas others have found equivalent or poorer responses.^94,95 The European recommendation only uses levofloxacin in the rescue regimen, when the results of antibiotic therapy are available.²⁰ When first-line therapy fails, the Maastricht IV Consensus Report recommends that bismuth-containing quadruple therapy can be a choice for second-line therapy.⁸ Many studies have investigated levofloxacin based regimens as second-line treatments, including meta analyses.⁹⁶

Generally, resistance to levofloxacin is low (<19%) worldwide. The rate of the primary levofloxacin resistance varies in the world’s regions and increases in Asian (25.28%) and South America (21.23%) higher than that in Africa and Europe (<15%). In Asia, the rate of levofloxacin resistance also varies in different countries: Japan (57%), Korea (24.55%), Iran (5.3%), and Malaysia (2.6%).⁸⁸

In Vietnam, a majority of the studies focused in the South Vietnam^16,33–35 and their results indicated that the rate of the primary levofloxacin resistance ranged from 18.4% to 35.6% (Table 3). The rate of the primary levofloxacin resistance increased from 18.3% in 2013 to 41.2% in 2015 in Ho Chi Minh City (Table 5).^16,33 The rates of the secondary levofloxacin resistance after 1, 2 and 3 treatments were 25.7%, 23.3%, and 33.3% respectively (Table 4).⁸¹ Phan et al.³⁴ found that the rates of the primary and secondary levofloxacin resistance were very high and 35.6% and 63.2%, respectively (p<0.05). Other fluoroquinolones such as nalidixic acid, ciprofloxacin and ofloxacin, which are commonly used in Vietnam, may lead to cross resistance with levofloxacin. Because the rate of levofloxacin resistance increased, so levofloxacin is not used much in H. pylori eradication in Vietnam.

8. Multidrug resistance patterns of H. pylori in Vietnam

Multidrug resistance has recently appeared as a serious challenge in the fight against infections in over the world. H. pylori strains harboring triple or quadruple resistance can hinder the choice and success of the eradication regimen. Binh et al.³³ showed that 33% (34 strains) of the isolates were the resistant to at least two antibiotics. Resistance to clarithromycin and metronidazole was most commonly observed (24.3%), and this may be the main reason for failure of treatment in Vietnam. Fig. 3 presents the multidrug resistance of H. pylori in Vietnam.

Fig. 3.

Multidrug resistance patterns of Helicobacter pylori in Vietnam. C+M, clarithromycin+metronidazole; C+L, clarithromycin+levofloxacin; C+T, clarithromycin+tetracycline; M+L, metronidazole+levofloxacin; M+T, metronidazole+tetracycline; L+T, levofloxacin+ tetracycline.

CAUSES OF ANTIBIOTIC RESISTANCE IN VIETNAM

1. Contributory factors

The contributory factors to treatment failure are multidimensional and complex. Host genetic factors, H. pylori virulent factors, antibiotic-resistant H. pylori strains, smoking habits, compliance to therapy and duration of therapy affect totally treatment outcome. In Vietnam, Dung et al.¹⁶ found that some causes as follows: wide use of antibiotics, incorrect dosage, quality of antibiotic, noncompliance of treatment protocol, bad habits (alcohol and tobacco consumption), mutation of H. pylori.

In fact, arbitrary use antibiotics (without a prescription, increase dose arbitrarily) is a common problem in Vietnam and might leading to the development of new antibiotic-resistant H. pylori strains. In addition, bad habits such as alcohol, beer, smoking can also affect the effectiveness of H. pylori eradication.

Several studies have examined the relationship between risk factors and the frequency of primary and secondary resistance of H. pylori. Risk factors should be analyzed include: age, gender, history of previous eradication treatment, smoking, occupation, type of residence, etc. Lee et al.⁸⁵ showed that “previous eradication” was an independent risk factor for the development of clarithromycin (p<0.001), azithromycin (p<0.001), levofloxacin (p=0.003) and moxifloxacin (p=0.006) resistance. District: “rural area” was an independent risk factor for the development of azithromycin (p=0.049) resistance. Job: “no occupation” was an independent risk factor for the development of azithromycin (p=0.034) resistance. However, other risk factors (gender, disease, alcohol, smoking, and socioeconomic) was not related to antimicrobial resistance of H. pylori.

In Vietnam, there are very few studies on the risk factors associated with H. pylori resistance. Recently, Hue⁸² studied the relationship between risk factors and H. pylori resistance. Research results showed that “age ≥30” and “previous eradication” was an independent risk factor for the development of clarithromycin. However, no correlation was found with levofloxacin (Table 6).

Table 6.

Multivariate Analysis of Predictors for Helicobacter pylori Resistance

Antibiotic	Parameter	Multivariate analysis
		OR (95% CI)	p-value
Clarithromycin (n=153)	Age ≥30 yr	3.2 (1.3–7.7)	0.011
	Previous eradication	7.7 (1.7–34.7)	0.008
Levofloxacin (n=154)	Age ≥40 yr	1.9 (0.9–3.7)	0.057
	Previous eradication	1.4 (0.6–3.1)	0.386

OR, odds ratio; CI, confidence interval.

2. Gene mutation of H. pylori related to antibiotic resistance

Two techniques applied clinically to define the antibiotic resistance to H. pylori comprise H. pylori culture and resistance regimen.⁹⁷ However, culturing H. pylori bacteria is very difficult, obtains low positive rate and requires long time; and not establishments can do it. To add these methods, at present, gene mutation of H. pylori bacteria with different antibiotics is defined. In Vietnam, initial studies of gene mutation of H. pylori bacteria related to antibiotic resistance (clarithromycin and levofloxacin) have been conducted.^98–102 There are a total of five studies of gene mutation of H. pylori bacteria related to antibiotic resistance (one study in the North Vietnam,⁹⁸ two studies in the Central Vietnam,^77,78,102 and two studies in the South Vietnam^35,100).

Toan et al.⁹⁸ showed two types of gene mutation in two positions detected: A2143G (26.7%), A2143T (6.7%), and T2182C (80.0%). Two types of gene mutation combined on a patient were A2143G+T2182C and A2143T+T2182 at the respective rates of 13.3% and 6.7%.

Phan et al.³⁴ studied gene mutation of H. pylori bacteria with clarithromycin and levofloxacin in Hue (Central Vietnam). Study results pointed that the mutation rate of A2143G was 85.7% (30/35) in the strain of bacteria resisted to clarithromycin. Similarly, the study of Doanh et al.¹⁰² also showed the mutation rate of A2143G was very high: 40 out of 41 (97.6%).

Trung et al.¹⁰⁰ studied gene mutation on 30 strains of H. pylori bacteria resisted to clarithromycin and 31 strains of H. pylori bacteria resisted to levofloxacin. Study results indicated 96.7% strains of H. pylori bacteria mutated with clarithromycin and 54.8% strains of H. pylori bacteria mutated with. The mutation rate with clarithromycin and levofloxacin was 56.7%.

However, gene mutation of H. pylori bacteria with clarithromycin in Vietnam is a controversy.¹⁰² While continuously studying situation and causes of the antibiotic resistance to H. pylori, applying the latest consensus (Maastricht V/Toronto) is extremely necessary. Selection of the regimens, combination of PPI doses and time, and H. pylori tests (culture, PCR and study of gene mutation of H. pylori) plays an importance role for efficiency of H. pylori eradication.

PERSPECTIVES FROM VIETNAM ASSOCIATION OF GASTROENTEROLOGY FOR DIAGNOSIS AND TREATMENT OF H. PYLORI INFECTION

In Vietnam, from 1990 to 2010, triple therapy (PPI + combination of two antibiotics) was used clinically for eradication with H. pylori. However, after more than two decades, the antibiotic resistance to H. pylori has increased by time. Based on International Consensus (Maastricht IV)⁸ and based on the increasing resistance of H. pylori to antibiotics in Vietnam, Vietnam Association of Gastroenterology has established a consensus on H. pylori eradication (June 2012 in Ho Chi Minh City).⁶⁷ The followings are some main contents related to H. pylori eradication:⁶⁷ (1) treatment regimens and duration (Table 7); (2) provide treatment recommendations for areas with increased rates of resistance.

Table 7.

Helicobacter pylori Eradication Regimens in Vietnam⁴⁵

	Regimen	Duration of therapy
Triple therapy	PPI+A+C	7 Days
Sequential therapy	First 5 days: PPI+A	5 Days
	Next 5 days: PPI+C+Ti	5 Days
Concomitant therapy	PPI+A+C+M/Ti	10 Days
Bismuth quadruple therapy	PPI+M+Te+B	14 Days

PPI, proton pump inhibitor; A, amoxicillin; C, clarithromycin; Ti, tinidazole; M, metronidazole; Te, tetracycline; B, bismuth.

Recommendation 25: First-line therapy for H. pylori eradication: Because the rate of antibiotic resistance in the North Vietnam and the Central Vietnam is lower than that in the South Vietnam, the triple therapy (PPI+A+C for 10 to 14 days) is recommended to be applied in this region (grade of recommendation B; agreement: 76%). In the South Vietnam, due to high rate of antibiotic resistance, sequential therapy regime or quadruple therapy (with/without bismuth) for H. pylori eradication (grade of recommendation B; agreement: 83%).⁶⁷

Recommendation 26: Second-line therapy for H. pylori eradication: (1) Use Bismuth quadruple therapy if it has not yet been used before (grade of recommendation A; agreement: 97%). (2) Use PPI+A+L triple therapy if Bismuth quadruple therapy was used but unsuccessful (grade of recommendation A; agreement: 93%).⁶⁷

However, recent data indicate that primary and secondary resistance of H. pylori to clarithromycin, metronidazole and levofloxacin is increasing.^33–35 This is of concern and suggests two important principles when prescribing a therapy in Vietnam: (1) clarithromycin-based or metronidazole-based triple therapy might not be useful as first-line therapies; (2) levofloxacin-based triple therapy should not be used as an alternative treatment. Therefore, first-line strategies such as bismuth-based quadruple or non-bismuth-based quadruple therapy should be recommended for Vietnamese infected patients.

In addition, it is necessary to apply techniques such as bacterial culture, antimicrobial susceptibility, gene mutation study of H. pylori is very necessary. The Maastricht V Consensus showed that treatment regimens for areas with clarithromycin resistance >15% and <15%.⁶⁹ Based on this, Vietnam Association of Gastroenterology needs to have a new consensus, to improve the effectiveness of H. pylori eradication in the future.

CONCLUSIONS

Vietnam has high rate of H. pylori infection in community as well as in gastric duodenal diseases (chronic gastritis, gastric ulcer, duodenal ulcer, and gastric cancer). In Vietnam, in early 1990s, rate of H. pylori eradication exceeded 90%. But, recent statistics indicated that rate of H. pylori eradication has reduced to 60%–70% and related to antibiotic resistance of H. pylori. The rate of metronidazole, clarithromycin and levofloxacin resistance has been increasing. Application of the recommendations from the International Consensus (Maastricht V/Toronto) is extremely necessary to improve efficiency of H. pylori eradication.