Eradication of Helicobacter pylori infection with standard triple therapy has been accepted to curb associated risks of chronic gastritis andpeptic ulcer disease.
To assess H. pylori eradication rate of standard triple therapy and patient related factors affecting eradication rate.
A facility based prospective follow up study was conducted in Bahir Dar City Administration, Ethiopia, on consented outpatients presented with gastritis and peptic ulcer disease and positive for H. pylori stool antigen test from May 2016 to April 2018. Eradication was confirmed with stool antigen test made after 4–6 weeks of standard triple therapy, comprising of proton pump inhibitor, clarithromycin and amoxicillin. Pre-developed questionnaire and data collection formats were used to collect variables before and after therapy. Bivariate and backward stepwise multivariate logistic regression was used to analyze data. P-value < 0.05 at 95%CI was considered as significant.
The overall H. pylori eradication rate was 90.3% (379/421). Almost 80% of the patients were urban residents. Mean (±SD) age and body weight of patients were 30.63 (± 10.74) years and 56.79 (± 10.17) kg, respectively. Self-reported adverse drug effects and area of residence of patients were factors affecting eradication rate significantly. Patients with no self-reported adverse drug effect were 3.85 (AOR: 3.85; 95%CI (1.41–5.26)) times more likely to eradicate H. pylori infection compared to those reported adverse effects. Patients living in rural area were 2.7 (AOR: 2.7; 95%CI (1.19–20.0)) times more likely to achieve eradication compared to urban residents.
H. pylori eradication rate is within the recommended level for clinical practice, indicating that modifications of the standard triple therapy observed in the different healthcare institutions are not evidence-based. Emphasis should be given to adverse drug effects of medications and tailored counseling based on area of residence could have a contribution in improving eradication rate.
Citation: Gebeyehu E, Nigatu D, Engidawork E (2019) Helicobacter pylori eradication rate of standard triple therapy and factors affecting eradication rate at Bahir Dar city administration, Northwest Ethiopia: A prospective follow up study. PLoS ONE 14(6): e0217645. https://doi.org/10.1371/journal.pone.0217645
Editor: Yan Li, Cleveland Clinic, UNITED STATES
Received: February 4, 2019; Accepted: May 15, 2019; Published: June 4, 2019
Copyright: © 2019 Gebeyehu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files.
Funding: The authors would like to acknowledge Addis Ababa University and Bahir Dar University for funding this research project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Helicobacter pylori infection remains one of the most common chronic bacterial infections affecting humans with prevalence rates varying widely among different geographical regions and ethnic groups [1, 2]. H. pylori infection causes chronic gastritis and is associated with an increased risk of upper gastrointestinal diseases, such as peptic ulcer disease, gastric cancer, and mucosa-associated lymphoid tissue lymphoma [3,4]. Eradication of H. pylori thus decreases the risk for gastrointestinal disease and is important to promote public health, especially in areas with high H. pylori prevalence.
Proton pump inhibitor (PPI)-based triple therapy is the mainstay therapy for eradication of H. pylori infection, although the regimens differ in combination of the antimicrobials used and duration of therapy. Specifically, PPI-based triple therapy, usually consisting of a PPI, amoxicillin, and clarithromycin, is a widely recommended regimen for H. pylori treatment in areas where clarithromycin resistance is low [5–8]. Accordingly, this regimen continues to be the recommended first-line treatment for H. pylori in Ethiopia. Its eradication rate has, however, not been studied. Moreover, the practice of sequential therapy is not uncommon in some healthcare institutions within the region, without supporting evidence.
An accumulating body of evidence also indicates that patient related factors, including poor compliance and antibiotic resistance are associated with eradication failure [9–11]. However, the relationship between eradication failure and other factors related to socio-demographic and clinical characteristics of patients are still a subject of controversy [12–14] and need further investigation. In addition, it is not uncommon to use some food items either alone or in combination with the triple therapy, usually in people with complaint of acid pepsin disorder. The common food items used in the study area are mucilage of Flaxseed or Linseed (Linum Usitatissimmum) and Fenugreek (Trigonella foenum-graecum), which are known as Telba and Abish, respectively, in the local Amharic language. Although there are several nutritional and animal studies supporting the protective or healing effect of these plants in gastritis and peptic ulcer [15–19], there are no studies done on the effect of these food items on eradication rate of H. pylori. Thus, the present study sought to address such issues that appropriate measures could be taken in the fight against H. pylori infection.
The study was approved by the Institutional Review Board of College of Medicine and Health Sciences, Bahir Dar University (Reference No: BCS/171/08). Permission was sought from the health institutions after presentation of the ethical approval. All the drugs used in eradication therapy were approved by Food, Medicine, Healthcare Administration and Control Authority (FMHACA) of Ethiopia and the treatment protocol is as per the national General Hospital Guideline. Patients were informed about the benefits and risks of the study as well as their full right to withdraw from the study at any time in point without jeopardizing the care they receive from the health facility. Moreover, privacy and confidentiality were maintained through anonymity and restricting data access S1 File.
Study design and setting
A facility based prospective follow up study was conducted from May 2016 to April 2018 in Bahir Dar, the capital city of Amhara Regional State, located 565 kilometers Northwest of Addis Ababa, the capital of Ethiopia. The study was conducted at two healthcare institutions, Adinas General Hospital and Kidanemihret Higher Clinic, which were selected based on the practice of using stool antigen test for diagnosis of H. pylori.
Patients and eradication therapy
The study was conducted on 421 H. pylori positive patients living in rural and urban settings. Volunteer adult (age ≥18 years) outpatients, who had agreed to give written consent and willing to come back following completion of triple therapy (4–6 weeks) for checking eradication were included in the study. Those who were seriously sick or referred from other facilities as well as those who do not speak the local language (Amharic) were excluded from the study. There were two encounters with the patients: the first was at the time of diagnosis, a time when they were recruited, and the second was at the completion of eradication therapy.
Both primary diagnosis as well as eradication of H. pylori after 4–6 weeks therapy was confirmed by a stool antigen test, which is recommended by both European and Japanese guidelines . Stool antigen test has the advantage of being a direct and noninvasive test because it detects either the bacteria or part of it (DNA, antigen) in an easily obtained specimen. Review studies reported sensitivity and specificity of the test to range from 88.8%-91.8% and 94.1%-94.5%, respectively [21,22]. Collection of stool sample was made with stool cup. The collected sample was immediately delivered to the respective clinical laboratory of the healthcare institutions and laboratory testing was conducted according to the Manufacturer’s recommendation (SD BIOLINE H. pylori Ag, Standard Diagnostics, Inc. Korea). H. pylori positive adult outpatients were treated by internists with a PPI-based triple therapy: omeprazole 40 mg or pantoprazole 40 mg, twice/day for 15 to 30 days); clarithromycin (500 mg), and amoxicillin (1000 mg), each twice/day for 10 or 14 days.
Data collection and management
Structured questionnaire developed from the literature was used to collect data in both the recruitment and follow up phases S1–S4 Tables. Patients’ sociodemographic and medical information was collected during the first encounter and data on drug utilization, adverse drug effects, and added-on therapy (homeopathic medicines) was collected during the follow up period. Phone calls were made to most patients to remind their appointment period.
Pre-test of the questionnaire was done on 5% of the sample size in another healthcare institution in the study area to ensure whether the questionnaire was able to capture the required information and modifications were made accordingly. Data was collected by trained clinical pharmacists and nurses. Data accuracy and consistency was assured by the study team on daily basis through direct supervision of data collectors and inspection of collected data.
On completion of therapy, stool sample was collected to determine the success or failure of H. pylori eradication therapy. Therapy was considered as successful on having negative stool antigen test following 4 to 6 weeks of eradication therapy, whereas positive result was taken as eradication failure. The latter patients were made to consult their physician for further evaluation and treatment.
Data were entered and analyzed using SPSS statistical package version 21.0. Descriptive statistics such as percentages, means and standard deviations were used to describe data. Chi-square test was used to assess failure-success differences in H. pylori eradication. Bivariate and multivariable logistic regressions were used to identify predictors of failure of eradication using triple-therapy. The Hosmer-lemeshow test was checked to assess the model fitness to conduct logistic regression. Each variable which fulfilled the Hosmer-lemeshow test on binary logistic regression (variable with no significant difference between observed and expected values) was retained for multivariable logistic regression. Backward stepwise logistic regression model was used during multivariable logistic regression to control confounding effect. Odds ratio with 95% confidence intervals was calculated for each of the independent variables using P-value < 0.05 as the level of significance.
From a total of 526 consented patients, 421 were able to come back to the healthcare institution for stool antigen test after eradication therapy. As shown in Table 1, the mean age (SD) of patients was 30.63 (± 10.74) years, which ranged from 18–86. More than 70% of patients were under 35 years old. The mean weight of patients was 56.71 (±10.19) kg and the mean body mass index was 21.09 (±4.16).
As shown in Table 2, two-third of the patients were females and majority (80%) of them were urban dwellers. Close to two-third (63.4%) of them were married and a sizable proportion (42%) of them attended college education or above. Around 38% of the patients were employees of government and private sectors with monthly paid salary and the rest were engaged in own income generating activities. Majority (86%) of the patients were followers of Ethiopian Orthodox Church.
Medical information and Helicobacter pylori eradication rate of patients
Medical information and H. pylori eradication rate of standard triple therapy of the study participants is summarized in Table 3. More than half (56%) of the patients confirmed that they had visited other healthcare institutions for seeking medical care before current eradication therapy, but they did not know the type of therapy they had taken. Almost 85% of them said that they had been living with their gastrointestinal complaint for more than a month. Almost half (50.5%) of the patients responded that they had felt pain after meal, while 29% reported that the pain feeling persisted throughout the day. About a fourth (25.6%) of them were living with chronic diseases and 56.3% were taking alcohol before initiation of the triple therapy.
Almost a third (32.1%) of the patients reported that they had taken diets traditionally believed to have healing effect on gastritis and peptic ulcer disease like Fenugreek and Flaxseed together with the triple therapy. These diets appeared to be commonly used by urban (34.2%) than rural (23.5%) patients. Almost a fourth (26.1%) of the patients responded that they had experienced adverse drug effects while taking medications and were unable to take their medication properly. Commonly reported adverse effects included, among others, gastrointestinal upset (16.4%) (nausea and vomiting, diarrhea, indigestion, and change in bowel habit) and headache (3.5%). Self-reported adverse drug effects were more in urban patients (28.3%) than rural ones (17.5%). Self-reported adverse drug effects among patients who used either Fenugreek or Flaxseed was comparable with patients that had not used these diets (25.9% vs. 26.2%).
The overall H. pylori eradication rate (success of therapy) was 90.02%. Pantoprazole (73.2%) was the most commonly used PPI over omeprazole (26.6%). Nearly two-third (66.3%) of the patients received PPI-based triple therapy for a duration of 10 days, whereas the remaining took for 14 days. No significant difference was noted in both H. pylori eradication rate and development of adverse drug effects between patients receiving therapy for 10 and 14 days.
The mean age of patients on whom H. pylori eradication was successful and unsuccessful was 30.64 (±10.72) and 30.63 (±10.87), respectively. The mean weight of patients before and after eradication therapy was 56.71 (±10.19) and 56.79 (+10.17) kg, respectively.
Factors associated with H. pylori eradication rate
Bivariate and multiple logistic regression analysis is depicted in Table 4. On bivariate logistic regression analysis, three variables: rural residence (COR: 5.61, 95%CI (1.33–23.69), p = 0.019); secondary educational status (COR: 0.38, 95CI (0.16–0.89), p = 0.025); and self-reported adverse drug effects (COR: 2.92 95%CI (1.52–5.59); p = 0.001) were significantly associated with failure of H. pylori eradication therapy. On multivariable logistic regression model analysis, rural residence and self-reported adverse drug effects were factors affecting eradication therapy. Those patients living in rural area were 2.7 (AOR: 2.7; 95% CI (1.19–20.0) (p = 0.032)) times more likely to eradicate H. pylori infection with triple therapy compared to those living in urban area. Patients without adverse drug effect were 3.85 (AOR: 3.85; 95% CI (1.41–5.26) (p = 0.002)) times more likely to eradicate H. pylori infection with triple therapy compared to those patients with adverse effects.
The aim of this study was to assess H. pylori eradication rate and determine the factors affecting eradication therapy. The overall H. pylori eradication rate of standard triple therapy was 90.02%. There are no similar studies conducted in the country to compare with the present result. However, varied rates have been reported from studies performed elsewhere. For example, rates similar with the present study (85–94%) are reported in some studies . But, lower rates (61–77%) are also reported in other studies . Adherence to therapy and resistance of H. pylori have been suggested to be the most important factors in H. pylori eradication therapy. Optimum eradication rate of H. pylori infection can only be achieved if adherence to drug therapy is higher in susceptible areas. It has been repeatedly reported that factors leading to poor adherence have paramount importance to determine successful treatment outcomes[25,26]. Thus, it is plausible to assume that the eradication rate differences could be associated with extent of adherence of patients to prescribed medications and/or local susceptibility pattern of H. pylori in the study areas. Considering these variability across regions, a meta-analysis has recommended that choice of antibiotics should be localized .
The standard triple therapy comprising of PPI, clarithromycin, and amoxicillin or metronidazole has become universal, as all of the consensus conferences and guidelines worldwide recommend this treatment for H. pylori eradication . An eradication rate of over 90% has been regarded as the optimal eradication cut-off therapy for per-protocol analysis . The effectiveness of H. pylori infection eradication therapy regimens, as per-protocol analysis, has been stratified based on the rate as excellent (>95%), good (91%-95%), borderline (85%-89%), and unacceptable (<85%) . In view of this suggestion, the present eradication rate is closer to good, indicating that the therapy is effective. Better eradication rate in the present study could be explained by: i) higher dose of therapy in relation to lower mean body weight of the patients; ii) longer duration of therapy, 10–14 days compared to 7 days therapy; and iii) low rate (6%) of resistance to amoxicillin and complete susceptibility for clarithromycin . According to a systematic review, worldwide prevalence of resistance to amoxicillin and clarithromycin was 11.2% and 17.2%, respectively , which is higher than the above mentioned figure reported in Ethiopians.
Of the possible variables assessed in the present study, only area of residence and self-reported adverse drug effects were factors that significantly affect H. pylori eradication rate. Patients living in rural areas were more likely to eradicate H. pylori infection than those living in urban areas. This is the first study to report the effect of residence on eradication and hence it is not possible to relate it with the literature. However, it could be associated with lower proportion of self-reported adverse drug effects in patients from rural area (17.5%) compared to urban area (28.3%). Obviously, eradication rate among patients with little or no adverse drug effects is higher than those who report more adverse drug effects, as there is better adherence with the former than the latter.
The percentage of self-reported adverse drug effects (26.1%) in the present study is higher than some (10–18%) [33–35] and lower than others (48–76%) [24,36] previously published studies. The difference could be due to several factors such as duration of triple therapy, socio-demographic differences of patients, pharmacogenetic variability among patients, drug combinations and possible interactions among these factors.
It is suggested that the efficacy of most H. pylori eradication regimens can be improved through use of potent acid secretion inhibitors, higher doses of antibiotics, and increasing duration of triple therapy [37, 38]. In this study, duration of triple therapy did not have influence on eradication rate. Likewise, no apparent difference in effectiveness was observed between omeprazole and pantoprazole-based therapy, confirming alternative use of the two drugs.
Age and sex were not significantly associated with eradication therapy as reported previously . Mean age of patients (30.63 years) in this study is comparable with previously reported mean age (28.8 years) in the same area, but lower than (40–53) studies done in other countries [36,41,42]. This indicates that the disease might be more prevalent in young adults. Percentage of female patients (65.6%) in the present study is comparable to previously reported prevalence of H. pylori infection among females in Ethiopia [43,44] as well as in other countries (62–65%) [34,41]. However, lower (28.6%)  and higher (75%)  prevalence in females has also been reported.
Alcohol did not affect eradication rate in this study and this is consistent with other studies [25,36]. There are different reports on effect of alcohol on H. pylori eradication, some reported as having effect on eradication, while others not. These differences could be due to differences in defining reported alcohol use and/or cultural differences of alcohol use in study populations.
Almost one-third (32.1%) of patients reported that they had taken diets traditionally believed to have healing effect on acid-pepsin disorder like Flaxseed or Fenugreek during therapy. In this study, use of either Flaxseed or Fenugreek had no significant effect on eradication rate. In line with this finding, diet was reported not to have effect on H. pylori eradication rate , although addition of fermented milk is reported to increase eradication .
Self-reported presence of other chronic diseases in this study was not a factor affecting eradication rate. Effect of other chronic diseases, such as diabetes mellitus, hypertension, chronic kidney disease, chronic liver disease, and chronic lung disease are thought to affect H. pylori eradication therapy occasionally, however, the results are inconsistent and the evidence is limited [47,48].
H. pylori eradication rate found in the present study is within the recommended level for clinical practice, indicating that modifications made in the standard triple therapy observed in different healthcare institutions, at least, in the study area are not based on evidence. Emphasis to adverse drug effects of medications and area of residence of patients during counseling could have contribution in improving eradication rate. Extending duration of therapy from 10 to 14 days or traditional supplementation practice of Flaxseed or Fenugreek by patients at home might not ensure success in the eradication therapy. Further studies on antibiotic susceptibility of H. pylori should be done to evaluate resistance as a factor in affecting eradication rate.
S1 Table. Sociodemographic data of Helicobacter pylori positive patients included in the study.
S2 Table. Response of Helicobacter pylori positive patients on first encounter.
S3 Table. Response of Helicobacter pylori positive patients on second encounter.
S4 Table. Format for laboratory result of patients on H. pylori eradication therapy research.
The authors would like to acknowledge Addis Ababa University and Bahir Dar University for funding this research project. We would like to thank Adinas General Hospital and Kidanemihret Higher Clinic for allowing data collection in their healthcare institutions. We would like to thank Abebe Fetene, Addisu, Mekonnen, and Kibret Ayalew for their administrative support during data collection. Finally, we thank volunteer patients for their involvement in this study project.
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