Randomized Clinical Trial on the Efficacy of Triple Therapy Versus Sequential Therapy in Helicobacter pylori Eradication

Abstract

Introduction:
Helicobacter pylori (H. pylori) colonization is prevalent all over the world, and it is associated with low socioeconomic status, poor hygiene, and overcrowding. Its eradication is important since it is an etiologic agent for gastritis, peptic ulcer, gastric carcinoma, and mucosa-associated lymphoid tissue lymphoma. Different regimens are available for the eradication of H. pylori and include triple therapy and sequential therapy. Our study aims to compare the efficacy of triple therapy versus sequential therapy in the eradication of H. pylori.

Material and methods:
This randomized clinical trial was conducted at the Pakistan Institute of Medical Sciences Hospital, Islamabad, from September 2016 to September 2017 after the approval of the institutional review board. A total of 160 patients were enrolled and equally divided into two, group A and group B. A twice-daily dose of amoxicillin 1,000 mg, rabeprazole 20 mg, and clarithromycin 500 mg was given to group A for 10 days, while group B was initially given rabeprazole 20 mg and amoxicillin 1,000 mg two times daily for the first five days (i.e., induction phase), followed by triple therapy that included rabeprazole 20 mg, clarithromycin 500 mg, and metronidazole/tinidazole 500 mg twice daily for the next five days. A negative stool antigen test performed four weeks after the completion of therapy was considered an effective eradication. A proforma was used to collect data that included age, gender, city or province of residence, family income, group (group A or group B), and eradication efficacy. Analysis of the data was performed using the Statistical Package for the Social Sciences version 17 (SPSS Inc., Chicago, USA).

Results:
A total of 160 patients were included, with mean age and standard deviation of 40.02±24.4 years. The male/female ratio was 1.8:1. Successful eradication of H. pylori achieved in group A was 67.5% (N=54) in comparison to group B, which was 95% (N=76) (p=0.001).

Conclusion:
Sequential therapy was superior to triple therapy in H. pylori eradication.

Full text

Review began 04/29/2022
Review ended 05/09/2022
Published 05/10/2022
© Copyright 2022
Sharif et al. This is an open access article
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Randomized Clinical Trial on the Efficacy of
Triple Therapy Versus Sequential Therapy in
Helicobacter pylori Eradication
Zain Sharif , Muaz Mubashir , Mehdi Naqvi , Hassan Atique , Saira Mahmood , Muneeb Ullah
1. Gastroenterology, Nishtar Hospital Multan, Multan, PAK 2. Internal Medicine, Federal Government Polyclinic
Hospital, Islamabad, PAK 3. Internal Medicine/Gastroenterology, Federal Government Polyclinic Hospital, Islamabad,
PAK 4. General Surgery, Maroof International Hospital, Islamabad, PAK
Corresponding author: Muneeb Ullah, muneebullah@gmail.com
Abstract
Introduction: Helicobacter pylori (H. pylori) colonization is prevalent all over the world, and it is associated
with low socioeconomic status, poor hygiene, and overcrowding. Its eradication is important since it is an
etiologic agent for gastritis, peptic ulcer, gastric carcinoma, and mucosa-associated lymphoid tissue
lymphoma. Different regimens are available for the eradication of H. pylori and include triple therapy and
sequential therapy. Our study aims to compare the efficacy of triple therapy versus sequential therapy in the
eradication of H. pylori.
Material and methods: This randomized clinical trial was conducted at the Pakistan Institute of Medical
Sciences Hospital, Islamabad, from September 2016 to September 2017 after the approval of the institutional
review board. A total of 160 patients were enrolled and equally divided into two, group A and group B. A
twice-daily dose of amoxicillin 1,000 mg, rabeprazole 20 mg, and clarithromycin 500 mg was given to group
A for 10 days, while group B was initially given rabeprazole 20 mg and amoxicillin 1,000 mg two times daily
for the first five days (i.e., induction phase), followed by triple therapy that included rabeprazole 20
mg, clarithromycin 500 mg, and metronidazole/tinidazole 500 mg twice daily for the next five days. A
negative stool antigen test performed four weeks after the completion of therapy was considered an
effective eradication. A proforma was used to collect data that included age, gender, city or province of
residence, family income, group (group A or group B), and eradication efficacy. Analysis of the data was
performed using the Statistical Package for the Social Sciences version 17 (SPSS Inc., Chicago, USA).
Results: A total of 160 patients were included, with mean age and standard deviation of 40.02±24.4 years.
The male/female ratio was 1.8:1. Successful eradication of H. pylori achieved in group A was 67.5% (N=54) in
comparison to group B, which was 95% (N=76) (p=0.001).
Conclusion: Sequential therapy was superior to triple therapy in H. pylori eradication.
Categories: Internal Medicine, Gastroenterology, Infectious Disease
Keywords: h. pylori, antimicrobial, eradication therapy, stool antigen, randomized trial, sequential therapy, triple
therapy, helicobacter pylori
Introduction
Helicobacter pylori (H. pylori) colonizes over 50% of the world population and about 70%-90% of the
population in developing countries [1,2]. Moreover, early acquisition of H. pylori, which often persists
lifelong, is attributed to low socioeconomic status, poor hygienic practices, and overcrowding [2]. It often
remains asymptomatic without any complications in up to 85% of individuals [3,4]. Furthermore, it is an
etiologic agent for a variety of upper gastrointestinal diseases with significant morbidity [5]. Its association
is well established with chronic active gastritis, atrophic gastritis, duodenal ulcer, gastric ulcer, gastric
adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma [3,6]. Helicobacter pylori can be
diagnosed by endoscopic histology, biopsy urease test, culture test, and polymerase chain reaction test of
the gastric biopsy specimen. Noninvasive tests include detection by fecal antigen assay, serology, and urea
breath test [4,7]. The stool antigen test has a sensitivity and specificity of 85%-95% [4]. The increasing
prevalence of antimicrobial resistance in H. pylori from person to person has led to the failure of eradication
therapy [8,9]. To avoid drug resistance, a combination of antibiotics is used instead of a single antibiotic [4].
Many international guidelines recommend triple therapy (clarithromycin, amoxicillin or metronidazole and
proton pump inhibitor (PPI), or ranitidine bismuth citrate) for 7-14 days as the first line of treatment for its
eradication [8,10]. A second-line therapy and antimicrobial treatment based on culture from a gastric biopsy
are reserved for failure of first-line therapy [8]. Despite a large number of studies, the single best therapeutic
regimen for the treatment of H. pylori could not be established. In trials, sequential therapy has shown
higher eradication rates than standard triple therapy [11,12]. However, management guidelines differ among
countries and depend on local susceptibility patterns [13]. A local study in Pakistan reported a high
clarithromycin resistance responsible for decreased H. pylori eradication with triple therapy [14]. Our study
1 2 3 2 4 4
Open Access Original
Article DOI: 10.7759/cureus.24897
How to cite this article
Sharif Z, Mubashir M, Naqvi M, et al. (May 10, 2022) Randomized Clinical Trial on the Efficacy of Triple Therapy Versus Sequential Therapy in
Helicobacter pylori Eradication. Cureus 14(5): e24897. DOI 10.7759/cureus.24897

aims to compare the efficacy of sequential therapy versus triple therapy in the eradication of H. pylori.
Materials And Methods
This randomized clinical trial was conducted in the Department of Gastroenterology of Pakistan Institute of
Medical Sciences Hospital, Islamabad, from September 2016 to September 2017. The ethical approval letter
numbered F. 1-1/2015/ERB/SZABMU was taken before the commencement of the trial from Shaheed Zulfiqar
Ali Bhutto Medical University. A simple random sampling technique was used. A total of 160 patients
presenting in the gastroenterology department were enrolled for this randomized clinical trial after
obtaining informed consent. Patients above the age of 18 years who tested positive for H. pylori by stool
antigen test were included in the study. Patients with a history of proton pump inhibitors or antibiotics
(within four weeks before stool antigen testing), gastric carcinoma, gastric surgery, chronic liver or renal
disease, chronic diarrhea, pregnancy, lactation, drug abuse, and poor compliance to medications were
excluded from the study. The patients were divided into two groups using the lottery method, group A and
group B, each containing 80 patients. A twice-daily dose of amoxicillin 1,000 mg, rabeprazole 20 mg, and
clarithromycin 500 mg was given to group A for 10 days, while group B was initially given rabeprazole 20 mg
and amoxicillin 1,000 mg two times daily for the first five days (i.e., induction phase), followed by triple
therapy that included rabeprazole 20 mg, clarithromycin 500 mg, and metronidazole/tinidazole 500 mg
twice daily for the next five days. The eradication course was followed four weeks later by a repeat stool
antigen test. A negative result was considered an effective eradication of H. pylori. Those who tested positive
were given an alternative treatment. A proforma was used to collect data that included age, gender, city or
province of residence, family income, group (group A or group B), and eradication efficacy. Patient
confidentiality was maintained. Analysis of the data was performed using the Statistical Package for the
Social Sciences version 17 (SPSS Inc., Chicago, USA). The frequency and percentage for qualitative variables
included efficacy and gender. Standard deviation and mean were calculated for the age of the patients.
Stratification was used to affect modifiers such as age and gender. Post-stratification chi-square test was
used. Its value of less than 0.05 with a 95% confidence interval was considered statistically significant.
Results
A total of 160 patients detected with H. pylori were included, with a mean age and standard deviation of
40.02±24.4 years. The minimum age was 18 years, while the maximum was 65 years. Male predominance was
seen with 64.6% compared to females who were 35.4%. The male/female ratio was 1.8:1. Age distribution in
terms of frequency and percentage is shown in Table 1.
Age category Number Percentage
18-20 3 1.8
21-30 25 15.6
31-40 32 20
41-50 47 29.3
51-60 41 25.6
61 and above 12 7.5
TABLE 1: Age distribution of patients
Most of the patients were residents of the federal capital of Islamabad, followed by Punjab and Khyber
Pakhtunkhwa. The geographical and socioeconomic distribution is shown in Table 2.
2022 Sharif et al. Cureus 14(5): e24897. DOI 10.7759/cureus.24897 2 of 5

Parameter Number Percentage
Place of residence
Islamabad (federal capital) 82 51.2
Punjab 29 18.1
Khyber Pakhtunkhwa 49 30.6
Family income per month
Less than 10,000 PKR 58 36.25
More than 10,000 PKR 102 63.5
TABLE 2: Geographical and socioeconomic parameters of patients
PKR: Pakistani Rupee
Successful eradication of H. pylori achieved in group A was 67.5% (N=54) in comparison to group B, which
was 95% (N=76) (p=0.001). Stratification according to gender and age is shown in Table 3.
Parameter
Triple therapy Sequential therapy
P-value
Eradication Number (%) Eradication Number (%)
Gender
Male (n=103)
Yes 40 (78.43) Yes 48 (94.1)
0.00031
No 22 (22.52) No 3 (5.8)
Female (n=57)
Yes 14 (49.1) Yes 28 (98.2)
0.00051
No 13 (45.6) No 2 (7)
Age
18-20 (n=3)
Yes 2 (60) Yes 3 (100)
0.000190
No 0 (0) No 0 (0)
21-30 (n=25)
Yes 12 (48) Yes 9 (36)
0.000231
No 6 (24) No 0 (0)
31-40 (n=32)
Yes 12 (37.5) Yes 16 (50)
0.00043
No 4 (12.5) No 0 (0)
41-50 (n=47)
Yes 19 (40.42) Yes 12 (25.5)
0.000623
No 13 (27.6) No 1 (2.1)
51-60 (n=41)
Yes 6 (14.6) Yes 28 (68.2)
0.000511
No 3 (7.3) No 2 (4.8)
61 and above (n=12)
Yes 3 (25) Yes 8 (66.6)
0.000111
No 0 (0) No 1 (8.33)
TABLE 3: Stratification according to gender and age
Discussion
The average presenting age in our study was 40.0±24.4 years. This was similar to a local study in Lahore with
40.51±13.04 years and an international study in Qatar with 38.85±11.78 years [11,15]. Male predominance
was seen in our study, which is consistent with a local study [16]. A significant proportion (36.25%) of the
population belonged to very low socioeconomic status with a monthly income of roughly 54 US dollars. This
is very low considering that the majority of patients are residents of the federal capital. Additionally, many
of them live in single room houses with average of five members in a family. Overcrowding along with a
poor hygienic environment and lack of basic facilities is directly related to the increased prevalence of H.
pylori [2]. The etiologic association of H. pylori with variety of gastrointestinal diseases mandates eradication
2022 Sharif et al. Cureus 14(5): e24897. DOI 10.7759/cureus.24897 3 of 5

therapy. This not only helps in the prevention of disease but also lessens the cost burden and morbidity and
increases the quality of life. In our study, successful eradication of H. pylori with triple therapy was seen in
67.5% of the patients, while successful eradication with sequential therapy was seen in 95% of the patients.
This was in accordance with other studies that showed sequential therapy to be more effective than triple
therapy [17-19]. The efficacy of triple therapy is decreasing, and the culprit held responsible is
clarithromycin resistance [20]. Still, sequential therapy is not the first-line therapy for eradication as
previous studies were unable to reach optimal results [21]. Additionally, the choice of second-line therapy
after failure of sequential therapy is yet to be standardized. On the contrary, there are other studies in which
sequential therapy was less effective [11,22,23]. The decreased efficacy of sequential therapy is secondary to
dual resistance associated with metronidazole and clarithromycin [24]. Modifications in management
guidelines are thus based on the locoregional efficacy of regimens and antimicrobial resistance. The main
factors affecting the regimen used and its efficacy include compliance of the patient, antimicrobial
resistance, drug brands, side effects of drugs, complex drug regime, especially in the case of sequential
therapy, and geographical area. Hence, while deciding the therapy regimen, one must take these parameters
into account. There were no significant side effects reported in our study. The stool antigen test for
detecting H. pylori is noninvasive and has good specificity and sensitivity [25]. Additionally, it was performed
in nearly all laboratories in regional area; therefore, it was used for the detection of H. pylori in our study. Its
cheap cost makes it affordable for private patients and lessens the burden on the government for those who
had their tests performed at our institute.
Our study lacked data on antimicrobial sensitivity and resistance, which is an important factor before
starting the therapy and determining its efficacy. However, it adds to the cost burden. Our study was limited
to a small proportion of patients. We did not standardize the brand names of medications that were used in
the study. Different brands have variable quality, cost, and efficacy. We also did not standardize the
laboratories for stool antigen testing. Both of these can affect the results.
Conclusions
Sequential therapy is superior to triple therapy in our community across all ages and gender for the
eradication of H. pylori. The stool antigen test is a noninvasive and effective test in determining the
eradication of H. pylori.
Additional Information
Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Shaheed Zulfiqar Ali
Bhutto Medical University, Pakistan Institute of Medical Sciences (PIMS), Islamabad, issued approval F. 1-
1/2015/ERB/SZABMU. After the evaluation of the project, unconditional permission is given to proceed with
this project. However, the committee reserves the right to discontinue the research study if reports are
received regarding the causation of undue risks/hazards to study subjects. Animal subjects: All authors
have confirmed that this study did not involve animal subjects or tissue. Conf licts of interest: In
compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services
info: All authors have declared that no financial support was received from any organization for the
submitted work. Financial relationships: All authors have declared that they have no financial
relationships at present or within the previous three years with any organizations that might have an
interest in the submitted work. Other relationships: All authors have declared that there are no other
relationships or activities that could appear to have influenced the submitted work.
Acknowledgements
We would like to acknowledge the services of Mrs. Yakhsha Anjum and the Cureus Editorial Team for their
critical review of the article.
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