Synergistic Dangers: Helicobacter Pylori and Cancer Genes

Y Usui et al. NEJM 2023; 388: 1181-1190. Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer

Background: Gastric cancer is the fifth most common neoplasm and the fourth leading cause of death from cancer worldwide.1 Helicobacter pylori has been classified as a group I carcinogen and is an environmental risk factor for gastric cancer.2 Although H. pylori infection affects more than half the world population

Methods: This study evaluated the association between germline pathogenic variants in 27 cancer-predisposing genes and the risk of gastric cancer in a sample of 10,426 patients with gastric cancer and 38,153 controls from BioBank Japan. This retrospective study also assessed the combined effect of pathogenic variants and H. pylori infection status on the risk of gastric cancer and calculated the cumulative risk in 1433 patients with gastric cancer and 5997 controls from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC).

Key findings:

  • Germline pathogenic variants in nine genes: (APCATMBRCA1BRCA2CDH1MLH1MSH2MSH6, and PALB2) were associated with the risk of gastric cancer.
  • At 85 years of age, persons with H. pylori infection and a pathogenic variant had a higher cumulative risk of gastric cancer than noncarriers infected with H. pylori (45.5% vs. 14.4%).
  • Limitation: The study population was from East Asia and thus, the findings may be different in other populations.

My take: H. pylori infection has a synergistic effect in increasing the risk of gastric cancer in individuals with germline pathogenic variants in homologous-recombination genes. To minimize the risk of gastric cancer, H pylori eradication is important; however, it is especially in those with cancer-predisposing variants.

From NEJM Twitter Feed

Related blog posts:

Understanding FDA Approval of Vonoprazan-Based Therapies for Helicobacter Pylori

Pharmacy Times (5/4/22): FDA Approves Pair of Vonoprazan Treatments for Helicobacter Pylori Infection

“The (FDA) has approved 2 vonoprazan-based medications for the treatment of Helicobacter pylori (H. pylori) infection.

Phathom Pharmaceuticals announced the approvals of both the Voquezna Triple Pak (vonoprazan, amoxicillin, clarithromycin) and Voquezna Dual Pak (vonoprazan, amoxicillin) based on positive safety and efficacy data from the phase 3 PHALCON-HP trial.”

WD Chey et al. Gastroenterol 2022; 163: 608-619. Open Access! Vonoprazan Triple and Dual Therapy for Helicobacter pylori Infection in the United States and Europe: Randomized Clinical Trial

Key findings from this randomized, controlled trial with treatment-naive 1046 adults:

  • In all patients, vonoprazan triple and dual therapy were superior to lansoprazole triple therapy (80.8% and 77.2%, respectively, vs 68.5% (both superior)
  • In patients with clarithromycin resistance, vonoprazan triple therapy was effective in 65.8%, dual therapy in 69.6%, vs lansoprazole triple therapy 31.9% (both superior)
  • Vonoprazan increases intragastric pH rapidly “and maintains it to a greater degree than PPI; this has been associated with higher H pylori eradication rates” (in prior studies as well)

The associated editorial: CA Fallone (Open Access!) The Current Role of Vonoprazan in Helicobacter pylori Treatment

Based on this new information, the author proposes the treatment algorithm below and notes that “the role of increased acid suppression by PPI substitution with vonoprazan should be examined in other H pylori regimens.” The author favors bismuth quadruple therapy in those with clarithromycin resistance as non-bismuth quadruple therapy utilizes an unnecessary antibiotic (clarithromycin).

Other points:

  • Metronidazole resistance is fairly common, but bismuth quadruple therapy can overcome much of the metronidazole resistance
  • Levofloxacin resistance is quite high in certain regions and should only be used with caution, given recent warnings from the US Food and Drug Administration of aortic rupture in susceptible individuals
  • Rifabutin can cause some bone marrow suppression

My take: With the more widespread availability of susceptiblity testing (beyond clarithromycin), I anticipate more targeted treatments. At the same time, vonoprazan-based treatments are likely to be important in increasing eradication rates.

Related blog posts:

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Why Is There Low Adherence to H pylori Guidelines?

S Bonilla et al. JPGN 2021; 73: 178-183. Low Adherence to Society Guidelines for the Management of Helicobacter Pylori Among Pediatric Gastroenterologists

This retrospective study with 250 patients determined that clinicians at this large center (Boston Children’s) have a low rate of adherence to the NASPGHAN/ESPGHAN H pylori guidelines (JPGN 2017; 64: 991-1003).

Key findings:

  • Patient outcomes: 107/186 (58%) had resolution of symptoms after treatment; abdominal pain was the most common presenting symptom (67%)
  • 131 (62%) had documented followup visit and an eradication test
  • First-line treatment was most commonly amoxicillin, clarithromycin, and PPI (69%) (in those without sensitivity information, amoxicillin, metronidazole, and PPI are recommended in the guidelines)
  • Biopsy culture was sent in 3% of patients

In their discussion, the authors make a number of points:

  • Both pediatricians and gastroenterologists “are utilizing a ‘test and treat’ strategy rather than endoscopy-based diagnostic testing.” This along with low followup and low biopsy culture deviate from NASPGHAN guideline.
  • 77 of 256 patients had non-invasive testing prior to referral and in this subset, more than two-thirds of patients received a clarithromycin-based triple therapy before being referred; “this has a high likelihood of failure.”
  • The authors advocate endoscopy over empiric treatment but acknowledge some reasons why families may want to avoid endoscopy (interestingly the authors do not mention the cost of the procedure). They also note that H pylori culture is not widely available.

My take: There are several reasons why there is low adherence to NASPGHAN/ESPGHAN guidelines

  1. Treatment recommendations for initial triple therapy does not align with adult guidelines for quadruple therapy. Even the “rescue” therapies (Table 5), these pediatric guidelines do not recommend quadruple therapy. Yet, there is no indication that H pylori is more susceptible to treatment in children.
  2. Recommendations for susceptibility/antibiotic resistance testing (Table 1, #11) makes no sense if susceptibility testing is not available. Fortunately, PCR-based assays are making this easier recently.
  3. The absence of susceptibility testing and cost would favor empiric treatment over endoscopy as a first-line approach in those who have a reliable non-invasive test indicating infection along with symptoms suggestive of H pylori infection.

Related blog posts:

Adult Guidelines:

Other related posts

This is the treatment approach per pediatric guidelines; these recommendations
do NOT align with treatment recommendations in adults

How Bad is Reflux in Children with Esophageal Atresia?

A recent retrospective study (FWT Vergouwe et al. JPGN 2019; 69: 515-22) with 57 children with esophageal atresia (EA) found most children have a normal reflux index.

This study, analyzing data between 2012-2017, reviewed all 24-hour pH-impedance (MII) studies in children at ≤18 months and 8 year olds with EA.  “All children with EA born in our hospital are offered a 24-hour pH-MII study at the age of 0.5 years and 8 years.”  In this institution, PPI treatment is given for at least 6 months after surgery. Of the 57 in the cohort, 20 had completed pH-MII at <18 months of age and 32 at age 8 years.

Key findings:

  • In children ≤18 months of age, median reflux index was 2.6% (abnormal in 2), median number of retrograde boluses was 61 (62% nonacid, 58% mixed)
  • In the older cohort (~8 years of age), median reflux index was 0.3% (abnormal in 4) and median number of retrograde boluses was 21 (64% nonacid, 75% mixed)
  • Overall, 10 of 57 children (17.5%) had GERD with reflux index >7% (n=6) or positive SI/SAP (n=4).  The authors note that much higher rates of GERD have been found in prior studies.  If they included children with fundoplication who were considered as having GERD (prior to fundoplication), then the GERD rate was 32%.

My take: This study showed that reflux in this cohort of children with EA was similar to the general population and likely indicates that a substantial portion of patients with EA do not need indefinite PPI therapy.  In children with more complex EA, PPI therapy is likely to be more beneficial.

Related blog posts:

Recent (November 4th) GI-Related Tweets:

It is Getting Harder to Treat H pylori -Here’s Why

In a recent study (A Savoldi et al. Gastroenterol 2018; 155: 1372-82, editorial pg 1287), the authors conducted a systematic review and meta-analysis to examine the prevalence of antibiotic resistance to Helicobacter pylori. The authors identified 178 studies with 66,142 H pylori isolates. Tables 2 & 3 provide comprehensive data.

Key points:

  • In the Americas region, primary resistance to clarithromycin, metronidazole, levofloxacin and amoxicillin was 10%, 23%, 15%, and 10% respectively.
  • In the European region, primary resistance to clarithromycin, metronidazole, levofloxacin and amoxicillin was 18%, 32%, 11%, and 0% respectively.

Antibiotic resistance is increasing: 

  • In the Americas region, resistance in 2006-2008 compared to 2012-201 for clarithromycin, & metronidazole: 11%–>20%, 26%–>29% respectively.
  • In the European region, resistance in 2006-2008 compared to 2012-201 for clarithromycin, & metronidazole: 28%–>28%, 38%–>46% respectively.
  • “The resistance rates to clarithromycin, metronidazole, and levofloxacin have increased over time in all WHO regions.”  Other regions with data in study included Eastern Mediterranean, Southeast Asia, and Western Pacific.
  • In the study, the authors also “describe a clear significant association between antibiotic resistance and treatment failure.”

In their discussion, the authors note that the incidence of gastric cancer is higher in areas with increased antibiotic resistance.  Though there has been a decline in gastric cancer, “based on our data, we can hypothesize that this trend in reduction is expected to revert soon because available treatment can no longer guarantee a satisfactory eradication rate.”

From editorial:

  • H pylori is not one of those bacteria in which resistance develops as an epidemic by horizonatal transfer of mobile genetic elements…Resistance in H pylori only occurs unevenly by mutations…Fortunately, resistance occurs “very seldomly for …amoxicillin and tetracycline.”
  • Treatment failure is “almost 7 times greater (6.97) when the strain is clarithromycin resistant and even greater (8.18) when the strain is levofloxacin resistant.” Resistance to metronidazole confers a lesser degree of treatment failure risk: OR 2.52.

My take: This study provides some sobering news about H pylori prevalence and how it is becoming more difficult to treat.

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Pooled Prevalence of resistance to clarithromycin (2006-2016). This is from Figure 2. Sections B & C (not shown) provide similar graphic info for metronidazole and levofloxacin