Background: Helicobacter pylori (H. pylori) infection is the main cause of gastric cancer
(GC), and long-term process occurs from premalignant lesions to carcinoma. H. pylori
eradication during early stages of disease in young adults ("screen and treat")
significantly impacts GC favoring survival, disease reversal and molecular changes.
Effects of eradication therapy in affecting gut microbiome diversity and composition, and
increasing antibiotic resistance rates in commensal bacteria, appear to be transient in
most studies. The investigators have shown that infection is acquired mainly during the
first 5 years of life, most infected children remain persistently infected with low rates
of spontaneous eradication and persistently infected children have more abdominal
complaints and higher levels of pepsinogen (PG) II (marker of gastric damage). A pilot
eradication trial in persistently infected school-aged children showed that with
sequential triple therapy, eradication was achieved in 96.8% of children, and treated
children had a decrease in PG I and II levels compared to non-treated. The Investigators
propose a "screen and treat" strategy aimed at a transition age between childhood and
adulthood, in areas with intermediate-high gastric cancer prevalence, to assess efficacy
of eradication, its clinical and molecular benefits and potential microbial side effects.
Aims: The primary aim will be to determine the effectiveness of H. pylori eradication
therapy in 14-18 years old adolescents in three regions with nearly 20-25% persistence
rates, and determine the effect of eradication on clinical and serum biomarkers of
gastric disease/damage. The secondary aims will be to determine the effects of H. pylori
eradication therapy on antimicrobial resistance of potentially pathogenic enteric
bacteria, and on gut microbiome composition. Exploratory aims: To determine the presence
of clarithromycin resistance genes in H. pylori by stool analysis of children not
achieving eradication, and determine the effects of reinfection on clinical findings
indicative of gastric disease, and biomarkers indicative of "gastric damage", gut
microbiota composition and antimicrobial resistance of H. pylori and other potentially
pathogenic bacteria. Methods: The Investigators will invite, through contact with the
health and educational authorities of Colina, Temuco and Coyhaique, 14-18 year old
students until we reach up to 1000 adolescents enrolled. H. pylori screening test (Urea
Breath Test; UBT) will be offered, and adolescents with a positive test will undergo two
additional tests, separated by 30 days, in order to confirm infection persistence (at
least two positive tests). It is expected that 20-25% of adolescents screened to be
positive for H. pylori, of which over 90% will be persistently infected. 210 Subjects
with persistent infection will then be randomized 2:1 to receive either an antimicrobial
course targeting H. pylori eradication (7 days of lansoprazole and amoxicillin followed
by 7 days of lansoprazole and clarithromycin plus metronidazole) or no treatment.
Participants will be followed-up with UBT (1 month post treatment, and then every 6
months for the remaining surveillance period), gastroenterological evaluation (2 weeks
pre treatment, 1 month, 3 months, 9 months and 18 months post treatment), blood samples
and stool samples (2 weeks pre-treatment, 1 month and 6 months post treatment). A subset
of 60 non-infected students from each site will be followed-up in matched times. To those
subjects with persistent infection who do not receive treatment, the same eradication
regimen will be offered after they have completed the initial 6-month follow-up with
their blood and stool samples taken.
Serum gastric damage biomarkers will be assessed using GastroPanel® (PGI, PGII, Gastrin)
and ELISA commercial kits (VCAM-1, CXCL13). Escherichia coli and Enterococcus spp will be
cultured from stools samples, and resistance to 6 antimicrobials will be assessed by disk
diffusion method. H. pylori clarithromycin resistance gene will be amplified from stools
using nested-qPCR. Composition of gut microbiome will be characterized by amplification
and sequencing the 16SrRNA gene from stools, ant then bioinformatics analysis. Expected
results: The prevalence of persistent H. pylori infection will be around 20-25% in
adolescents from Colina, Coyhaique and Temuco. Eradication will be successful in >90% of
persistently infected students, and reinfection rates will not surpass 15% in a 2-3 year
period. Eradication will be significantly associated with a decrease in clinical findings
indicative of gastric disease, and a decrease in biomarker levels indicative of "gastric
damage". Treatment will have a transitory effect on increasing antimicrobial resistance
rates of potentially pathogen enteric bacteria (Escherichia coli, Enterococcus spp.).
Treatment will have a transitory effect on disrupting gut microbiota composition at
phylum, class, order, family and genus levels, which will be restored to levels
comparable to non-infected healthy teenagers at the end of follow-up. In those
adolescents for whom eradication therapy fails, clarithromycin resistance will be more
prevalent in pretreatment samples compared to those eradicating H. pylori; in reinfected
children, treatment will have a transitory effect on increasing detection rates of H.
pylori clarithromycin resistance genes.
