Helicobacter pylori Reinfection Is Common in Peruvian Adults after Antibiotic Eradication Therapy

Giselle Soto 2 Christian T. Bautista 1 Daniel E. Roth 2 Robert H. Gilman () 2 5 Billie Velapati no 0 Masako Ogura 4 Giedrius Dailide 4 Manuel Razuri 2 Rina Meza 1 Uriel Katz 2 Thomas P. Monath 3 Douglas E. Berg 4 David N. Taylor 1 the Gastrointestinal Physiology Working Group in Peru 0 0 Cayetano Heredia University , Lima , Peru 1 United States Naval Medical Research Center Detachment 2 Asociacio n Bene fica PRISMA 3 Acambis , Cambridge, Massachusetts 4 Department of Molecular Microbiology and Genetics, Washington University Medical School , St. Louis, Missouri 5 Department of International Health, The Johns Hopkins Bloomberg School of Public Health , Baltimore, Maryland To characterize posttreatment recurrence of Helicobacter pylori in Peru, 192 adults with H. pylori-positive gastric biopsy specimens were monitored by 14C-Urea breath test, after eradication of H. pylori by use of amoxicillin, clarithromycin, and omeprazole. The cumulative risk of recurrence at 18 months was 30.3% (95% confidence interval, 21.4%-39.3%). Randomly amplified polymorphic DNA patterns and DNA sequence data established that, among 28 pairs of H. pylori isolates from pretreatment and recurrent infections, 6 (21%) were genetically similar, suggesting recrudescence of the previous infection, and 22 (79%) were different, suggesting reinfection with a new strain that differed from that involved in the initial infection. Eating mainly outside of the home was a risk factor for infection with a new strain (adjusted relative risk [RR], 5.07), whereas older age was a protective factor (adjusted RR, 0.20). Although an increase in the anti-H. pylori IgG antibody titer corresponded to recurrence, pretreatment and recurrent infections were similar with respect to quantitative culture colony counts and histologic characteristics, suggesting that neither prior eradication nor the memory immune response measurably alters the risk or burden of recurrent infection. Although eradication with antibiotics was successful, the high rate of reinfection suggests that treatment is unlikely to have a lasting public health effect in this setting. - fection recurrence [17]. However, in many developing countries where the baseline prevalence of H. pylori infection is often as high as 70%90% [8], the longterm effectiveness of antimicrobial therapy may be limited by high rates of resistance to antibiotics and an elevated risk of posttreatment reinfection by strains transmitted from individuals in the household or community. Although some studies in settings of high prevalence of H. pylori (e.g., China and Malaysia) have demonstrated rates of recurrence that mirror those in developed countries [9, 10], most have reported rates that are moderately [1116] or substantially [1721] higher. H. pylori is one of the most genetically diverse bacterial pathogens [22]. This diversity potentially allows the use of molecular techniques to distinguish a reinfection (infection by a strain of H. pylori that differs from the pretreatment infection in the same host) from a recrudescence (reemergence of a strain that genetically matches the pretreatment strain, which thus may not have been fully eradicated, despite not being detected by immediate posttreatment testing). However, DNA-based analysis of strains from individuals in communities where the risk of infection is high may underestimate the actual rate of reinfection, since transmission is likely to be intrafamilial, and members of the same household often carry closely related strains [23]. In developed countries, recurrence of H. pylori usually has been considered to be due to recrudescence [8, 2427], but few studies have established the rates of reinfection in developing countries. A high rate of reinfection would imply that microbial transmission continues to be significant in adulthood, would be a crucial consideration in the design of eradication strategies, and would broaden our understanding of H. pylori epidemiology and genome evolution. In Peru, particularly within lower socioeconomic strata, where crowding and poor sanitation facilitate transmission of H. pylori, children are infected with H. pylori from a very young ageover 70% are seropositive by 5 years old [28, 29]and 90% of adults undergoing upper-gastrointestinal endoscopy to investigate symptoms of dyspepsia are found to be infected as well [30, 31]. Among individuals with chronic gastric inflammation, infection promotes the development of gastric adenocarcinoma, often in the absence of peptic ulcer disease [32]. In this high-prevalence setting, patterns of posteradication recurrence and the rate of true reinfection, among adults with H. pyloriassociated nonulcer dyspepsia (NUD), are unknown. Here, we have conducted an 18-month study of individuals with NUD after eradication of H. pylori, to determine the rates and determinants of recrudescence and reinfection, in a setting of high prevalence of H. pylori. We compared the identities of H. pylori strains recovered from individuals before and after antibiotic treatment, using randomly amplified polymorphic DNA (RAPD) polymerase chain reaction (PCR), as well as DNA sequencing of representative loci. Serial antiH. pylori antibody titers and quantitative culture of bacterial isolates, from pretreatment and recurrent infections, provided insight into the host immune response. SUBJECTS, MATERIALS, AND METHODS Setting The study was conducted between 15 April 1998 and 5 November 5 2000. Participants were residents of Las Pampas de San Juan de Miraflores, a pueblo joven (shanty town) on the outskirts of Lima, Peru, with a population of 50,000 residents in lower socioeconomic strata, that has been described elsewhere [29]. Subjects The study cohort has been described elsewhere [33]. A total of 276 volunteers, 1855 years old, with symptoms of dyspepsia were initially recruited by house-to-house visits (3 individuals were then excluded for the following reasons: !18 years old, human immunodeficiency virus [HIV]positive status, and allergy to penicillin). The presence of dyspepsia was assessed by use of a dyspepsia questionnaire previously validated in Lima [34], in which dyspepsia is defined as the occurrence, during the previous 15 days, of 2 of the following symptoms: feeling of fullness or bad taste after eating, burning sensation or acid taste in mouth, gastroesophageal reflux, nausea, vomiting, burping, and burning that improved with eating. Exclusion criteria were the following: breast-feeding; positive pregnancy test at enrollment (Pregnosticon; Organon Teknika); unwillingness to practice birth control for the period of treatment; physical or mental impairment; serious concomitant illness (including HIV/AIDS); another study participant in the same household; gastric cancer, active peptic ulcer disease, or known past history of Zollinger-Ellison syndrome; history of adverse reactions to any of the drugs used in the treatment regimen; or treatment with antibiotics, (...truncated)