Predictors of triple therapy treatment failure among H. pylori infected patients attending at a tertiary hospital in Northwest Tanzania: a prospective study

Helicobacter pylori is one of the most prevalent organism that can lead to erosions, ulcerations and cancers [1]. Overall the prevalence of H.pylori infection is about 44.3% worldwide and is more in developing countries than in developed countries [2]. The International Agency for Research on Cancer (IARC), which is part of the World Health Organization (WHO) declared H pylori as class I carcinogen [3].

H.pylori infected persons have a 10 to 20% lifetime risk of developing ulcer and a 1 to 2% lifetime risk of developing gastric cancer [4]. With increase resistance to clarithromycin worldwide there is an increased risk of first line H. pylori treatment failure [5, 6]. Treatment guidelines for the management of H. pylori infection differ among countries and depend on local susceptibility patterns [7]. The efficacy of standard 7 days therapy is decreasing globally [8, 9]. Eradication rates of H.pylori have been found to be less than 80% in some countries [10‐12]. The H. pylori treatment failure has been linked to infections with antibiotic resistant strains [13‐16], host genetic polymorphism in the cytochrome that may affect proton pump inhibitor pharmacokinetics (CYP2C19), poor adherence, short duration of therapy and smoking [17‐19].

Previous efforts to improve the eradication of H. pylori have focused on increasing the numbers and types of drugs in the regimens and prolongation of the duration of standard triple therapy, none of which achieved higher eradication rates [20‐22]. Other newer efforts include the implementation of concomitant (Proton pump inhibitor, amoxicillin, clarithromycin, and a nitroimidazole (tinidazole or metronidazole) given together for 3–10 days) and hybrid therapies (Proton pump inhibitor and amoxicillin for 7 days followed by another 7 days of Proton pump inhibitor, amoxicillin, clarithromycin, and a nitroimidazole) [23‐26]. These therapies have resulted in eradication rates of 85 to 94%, and are currently advocated in places with greater than 15% clarithromycin resistance [27‐30].

H. pylori treatment outcome and associated factors have not well been studied in East African countries. To-date there is the report of 10 patients who were investigated in 1999 from Ethiopia [12]. This study has provided the magnitude and factors associated with treatment failure in patients treated with first line regimen from developing country and has documented sensitivity and specificity of stool antigen testing within 7 days in detecting treatment failure. These information are very crucial in devising appropriate strategies to improve the outcome of H.pylori treatment.

Total of 353 participants were invited and participated in the study. A total of 213 dyspeptic patients who tested positive for H.pylori stool antigen were included in the study. Out of 213 patients who were H. pylori stool antigen positive (Fig. 1), 3/213(1.4%) were lost to follow up (one was transferred to another region, two patients decided to use local herbs). A total of 210 participants were followed to completion, their median age was 35 yrs. (IQR 27–48). The endoscopy findings of 210 participants indicated that the majority had gastritis/duodenitis (Table 1).

Standard H.pylori triple therapy has been a regimen of choice for many years. Unfortunately there is a decline in its efficacy hence clinicians have replaced standard triple therapy with sequential, concomitant and hybrid therapy (modified sequential) to increase cure rate [26, 37, 38]. It should be noted that the efficacy of standard triple therapies, which is still recommended in most guidelines, has decreased to < 80% in different countries [39‐44].

As a general standard for the treatment of H.pylori, the anti- H.pylori therapeutic regimens should have an eradication rate of ≥90% [45]. Here, we report an alarming treatment failure rate of over 30% among patients with H. pylori infection seeking medical care in a tertiary hospital, Tanzania. This study for the first time in Tanzania has documented the H. pylori first line treatment failure among patients who were not previously on antibiotic. The treatment failure reported in the current study is significantly lower than what was reported in Egypt, this could be explained by the choice of patients. In current study, dyspeptic patients included were not on antibiotics within 30 days before the stool test was done while in Egyptian study the patients included were those who presented with dyspepsia without considering the prior use of antibiotics [46]. It should be noted that secondary clarithromycin resistance has been found to be significantly higher than primary resistance [47]. When compared to a study in Rwanda which reported treatment failure of 20% [44], no specific reason was elucidated to explain this variations pointing to geographical differences in the magnitude of resistance. High resistance to clarithromycin draws the urgent need to change treatment strategies in order to improve the treatment outcome in our setting. In addition, more studies are needed to explore drivers of the resistance.

The efficacy of the first line treatment therapy for H. pylori is decreasing in different parts of the world [48, 49]. As observed in the current study, clarithromycin resistance has been implicated as the potential factor for the first line treatment failure in many studies [39, 42, 50‐52]. A study from Rwanda [44] also observed that clarithromycin resistance was a significant factor that predicted treatment failure. It should be noted that clarithromycin mutations often predict treatment failure of clarithromycin-based regimens [53, 54]. This was the case in the current study, with big odd ratio and 95% CI being reported due to the fact that there was significant more participants in the group with no mutation than that with mutation.

Good adherence has been found to predict good outcome of medication [42, 55‐57], this was also observed in the current study. Poor adherence always leads to the sub-therapeutic levels or sub-optimal dose resulting in poor clinical outcome [58]. Interestingly, a study looking at the role of adherence to medications found that close follow-up of patients did improve compliance and satisfaction for the patients but did not increase the H. pylori eradication rate [36, 59]. This might have been due to other factors like drug resistance which can affect the eradication of the infection. Despite age and sex being documented as factors associated with H. pylori treatment outcome, this was not the case in the present study [39] [60].

Standard practices for the management of H. pylori infection recommends that post treatment non-invasive tests to confirm the eradication of H. pylori must be performed 4 weeks or more after eradication therapy is completed. In current study, stool antigen test done within 7 days after treatment well predicted eradication and treatment failure (positive predictive value, 86.7%, with negative predictive value of 100%). This finding was also observed in the studies done in United States and Europe, whereby positive result on the stool antigen test 7 days after completion of therapy identified patients in whom eradication of H. pylori was unsuccessful [61]. These data suggest that earlier stool antigen follow-up testing would identify those who will fail therapy and allow early initiation of second-line treatment [62, 63].

About one third of patients with clarithromycin resistance mutations and poor adherence developed first line treatment failure. Stool antigen testing within seven days after completion of therapy can be considered in order to initiate second treatment early to prevent associated morbidities. Strengthening adherence counselling before and during treatment is crucial in ensuring treatment success. More effort is needed in developing countries to ensure individual tailored treatment basing on the susceptibility patterns is practised.