Next-Generation Treatment for H Pylori

KG Hulten, et al. Gastroenterol 2021; 11: 1433-1442. Open Access: Comparison of Culture With Antibiogram to Next-Generation Sequencing Using Bacterial Isolates and Formalin-Fixed, Paraffin-Embedded Gastric Biopsies

Background: “The general unavailability of culture-based susceptibility testing for H pylori has resulted in the almost universal reliance on hopeful (empiric) therapy and a high proportion of treatment failures.” Besides the lack of availability of culture-based susceptibility testing, the global increase in prevalence of antimicrobial resistance contributes to the poor cure rates obtained with empiric use of the currently most popular triple therapies for H pylori infection.

Methods: H pylori isolates (n=170) (clinical isolates and formalin-fixed, paraffin-embedded) were tested for susceptibility to amoxicillin, clarithromycin, metronidazole, levofloxacin, tetracycline, and rifabutin using agar dilution and NGS targeted to 23S rRNAgyrA16S rRNApbp1rpoB and rdxA. Agreement was quantified using κ statistics.

Key findings:

  • Agreement between agar dilution and NGS from culture isolates was very good for clarithromycin (κ = 0.90012), good for levofloxacin (κ = 0.78161) and fair for metronidazole (κ = 0.55880), and amoxicillin (κ = 0.21400)
  • Comparison of NGS from tissue blocks and agar dilution from isolates from the same stomachs demonstrated good accuracy to predict resistance for clarithromycin (94.1%), amoxicillin (95.9%), metronidazole (77%), levofloxacin (87.7%), and tetracycline (98.2%)

Associated editorial: F Megraud et al. Gastroenterol 2021; 11: 1367-1369. Open Access: Molecular Diagnosis for Helicobacter pylori . . . at Last

Excerpts from editorial:

  • “By targeting all of the genes responsible for antibiotic resistance, it is possible to obtain genotypic susceptibility data for all of the antibiotics of potential use, without the need to perform” culture and antibiotic susceptibility testing
  • “Hulten et al show not only that they obtained comparable results with the reference method (phenotypic) for most of the antibiotics, but also that NGS can also be performed on both culture isolates and stored histologic preparations. This result is important because it avoids the need for extra biopsies and culture”
  • “NGS could also be applied on stools. In this particular environment where H pylori DNA is found in a low amount, excellent DNA extraction methods are mandatory and progress is being made in this field”

My take: NGS can bring H pylori treatment to a new era (like almost all other infections). “Molecular methods can potentially augment or even replace the current in vitro methods for susceptibility testing, which are cumbersome, technically challenging, and time-consuming.”

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Expanding Treatment Population in Chronic Hepatitis B?

W-J Jeng. AS Lok. Clin Gastroenterol Hepatol 2021; 19: 2006-2014. Open Access: Should Treatment Indications for Chronic Hepatitis B Be Expanded?

In this review, the authors propose expanding treatment indications for chronic hepatitis B virus (HBV).

The authors review current guidelines (Table 2 lists the major society recommendations). For example, the AASLD recommends HBV treatment for the following:

  • Antiviral treatment in all patients with cirrhosis and detectable viremia, independent of alanine aminotransferase (ALT) or HBV DNA levels
  • For patients without cirrhosis, all guidelines recommend treatment in patients with immune active disease; treatment is mainly with a NA (nucleos(t)ide analog) until 1 year after confirmed HBeAg seroconversion for patients who were HBeAg-positive and until HBsAg loss for patients who were HBeAg-negative at the start of treatment
  • AASLD cut-offs for distinguishing immune active disease: ALT ≥2× ULN or evidence of significant histologic disease and HBV DNA >20,000 IU/mL for HBeAg (+) and >2000 IU/mL for HBeAg (–)

Why Expand Treatment Indications?

The main reason for advocating treatment of patients in the immune tolerant phase is the mounting evidence that persistently high viremia and persistent presence of HBeAg are associated with increased risk of cirrhosis, HCC, and liver-related mortality…In one study of 438 HBeAg-positive patients, the 15-year cumulative risk of cirrhosis and HCC increased from 3.7% and 2.1% in patients who seroconverted before age 30 to 12.9% and 3.2% in those who seroconverted between ages 30 and 40 and 42.9% and 7.7% in those who did so after age 40

Why Not Treat All Patients with Chronic Hepatitis B?

“An important reason for deferring treatment of patients in the immune tolerant phase is that spontaneous HBeAg and HBsAg clearance with remission of liver disease can occur.” This happens in 80% or more over 10-20 years.

Who Else Should Receive Treatment (Beyond Guidelines)?

“Available data support expanding treatment to immune tolerant patients and patients in the grey zones who have evidence of active/advanced liver disease based on liver biopsy or non-invasive tests and those who remain in the immune tolerant phase after age 40. Evidence supporting treatment expansion to confirmed inactive carriers and other immune tolerant patients is lacking.” “Grey zones” indicate that “the course of chronic HBV infection is characterized by fluctuations in HBV DNA and ALT levels, and many patients will be in the grey zone at some point.”

My take: Given the safety/tolerability of newer HBV treatments, these recommendations make sense. If/when HBV treatments improve further (higher loss of HBsAg or HBV DNA), then even more widespread use of HBV treatments would be worthwhile.

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Hyde Farm, Marietta GA

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Oral Treatment of Celiac Disease & Research Optimist

A long time ago I heard a joke from a mentor about how can you tell if a person is an optimist.  An optimist is a person who finds a pile of manure under the tree on Christmas morning and declares: ‘Oh boy, I’m getting a pony.’

Researchers who are trying to identify oral treatments for celiac disease are probably true optimists. Yet, despite my skepticism, a recent study (D Schuppan et al. NEJM 2021; 385: 35-45. A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease) provides the best proof yet that an oral treatment may be helpful.

In this 6-week randomized, double-blind, placebo-controlled study with 159 participants, treatment with ZED1227, a selective oral transglutaminiase 2 inhibitor reduced histologic injury compared to placebo; all patients were receiving a diet with 3 grams of daily gluten. Key findings:

  • Treatment with ZED1227 at all three dose levels attenuated gluten-induced duodenal mucosal injury. The estimated difference from placebo in the change in the mean ratio of villus height to crypt depth from baseline to week 6 was 0.44 (95% confidence interval [CI], 0.15 to 0.73) in the 10-mg group (P=0.001), 0.49 (95% CI, 0.20 to 0.77) in the 50-mg group (P<0.001), and 0.48 (95% CI, 0.20 to 0.77) in the 100-mg group (P<0.001)
  • The estimated differences from placebo in the change in intraepithelial lymphocyte density were −2.7 cells per 100 epithelial cells (95% CI, −7.6 to 2.2) in the 10-mg group, −4.2 cells per 100 epithelial cells (95% CI, −8.9 to 0.6) in the 50-mg group, and −9.6 cells per 100 epithelial cells (95% CI, −14.4 to −4.8) in the 100-mg group
  • Adverse events were similar to placebo; 3 (8%) patients in the 100 mg group developed a rash

The need for a treatment besides a gluten-free diet is significant; among adults, 40-50% do not achieve mucosal healing/recovery despite GFD institution; in addition, the diet is difficult and costly.

My take: I think it is still a long journey to find an effective & safe oral treatment for celiac disease.

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Lots of Room to Improve with H pylori Treatment

Briefly noted: A recent survey study (N Du et al. JPGN Reports: 2021; 2: p e033. doi: 10.1097/PG9.0000000000000033. Full Text: Assessment of Community Pediatric Providers’ Approach to Children With Helicobacter pylori) found that pediatric providers had poor knowledge and/or adherence to pediatric H pylori guidelines.

Key findings:

  • Over a third of the respondents reported incorrectly testing patients for H. pylori while they were taking proton pump inhibitors.
  • 17% (n=17) incorrectly preferred blood serology as testing modality
  • 63% (n=64) relied on symptom resolution as indication of cure

My take: It would be interesting to compare pediatric gastroenterology provider responses to general pediatric providers. It is likely that a much higher percentage would be following established guidelines. One area of the guidelines that I think should be changed would be encouraging increased use of quadruple therapy in children, especially if resistance testing is not performed; this change would better align with adult guidelines. In adults, quadruple therapy has been associated with increased cure rates.

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Clostridium difficile Guidelines

Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA)

Clinical Infectious Diseases, Volume 66, Issue 7, 19 March 2018, Pages e1–e48,https://doi.org/10.1093/cid/cix1085

Summary from Infectious Disease Advisor: Updated C difficile Infection Clinical Guidance From IDSA/SHEA

The comprehensive clinical practice guideline …was endorsed by the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA)…

Recommendations for treatment of CDI in adults… now favors a 10-day course of vancomycin or fidaxomicin rather than metronidazole for first-line therapy of mild/moderate CDI in adults… Fidaxomicin, also a newly recommended first-line therapy for mild/moderate CDI in adults, may reduce the risk for recurrent CDI because of its narrow spectrum compared with vancomycin.

Recommended treatment strategies for recurrent CDI, a complication that occurs in approximately 25% of patients, have also been revised…Following initial CDI treated with a 10-day course of vancomycin, either a several-week tapered and pulsed course of vancomycin or a 10-day course of fidaxomicin is recommended. For most patients, probiotics can be considered because of favorable cost and safety, although definitive efficacy data for probiotics to prevent recurrent CDI are still lacking. For multiply recurrent CDI (ie, at least 3 CDIs), correction of the patient’s underlying intestinal microbiota perturbation with fecal microbiota transplantation (FMT) should be strongly considered..

The diagnosis of CDI… Molecular tests (eg, nucleic acid amplification tests [NAATs], such as polymerase chain reaction), which do not differentiate colonization and infection, are now the most commonly used test for CDI among US hospitals. NAATs have the potential to misdiagnose patients with colonization as having CDI, particularly when used in patients with low likelihood of CDI. Thus, this guideline strongly reinforces the importance of practicing good diagnostic stewardship and limiting C difficile testing to patients with new-onset, unexplained, and clinically significant (ie, at least 3 unformed stools in a 24-hour period) diarrhea…formed stools should not be tested for C difficile, nor should patients be retested within 7 days of a previous negative C difficile test. In pediatric populations, because of the unclear role of C difficile as a cause of diarrhea in infants, children less than 12 months of age should not be tested…

If diagnostic stewardship is not an achievable goal, use of NAAT alone is likely to lead to frequent misdiagnosis of CDI among patients with C difficile colonization. In these cases, NAAT alone should be avoided and a multistep algorithm that incorporates toxin testing is recommended.

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Cumberland Island 2018

New Hepatitis B Treatment Guidelines

Link to full article: Updated Hepatitis B Treatment Guidelines from AASLD

With regard to pediatrics:

9A. The AASLD suggests antiviral therapy in HBeAg-positive children (ages 2 to <18 years) with both elevated ALT and measurable HBV DNA levels, with the goal of achieving sustained HBeAg seroconversion.

“Most studies required ALT elevation (>1.3 times ULN) for at least 6 months with HBV DNA elevations for inclusion. Given that HBV DNA levels are typically very high during childhood (>106 IU/mL), there is no basis for a recommendation for a lower-limit value with respect to treatment. However, if a level <104 IU/mL is observed, therapy might be deferred until other causes of liver disease and spontaneous HBeAg seroconversion are excluded.”

“Duration of treatment with oral antivirals that has been studied is 1-4 years. It may be prudent to use HBeAg seroconversion as a therapeutic endpoint when oral antivirals are used, continuing treatment for an additional 12 months of consolidation, as recommended in adults. It is currently unknown whether a longer duration of consolidation would reduce rates of virological relapse.”

“Children who stop antiviral therapy should be monitored every 3 months for at least 1 year for recurrent viremia, ALT flares, and clinical decompensation.”

9B. The AASLD recommends against use of antiviral therapy in HBeAg-positive children (ages 2 to <18 years) with persistently normal ALT, regardless of HBV DNA level.

Another nice summary of current treatment recommendations: P Martin et al. Clin Gastroenterol Hepatol 2015; 13: 2071-87.  Table 5 lists recommendations for treatment of HBeAg-positive.

  • The main group needing treatment (entecavir, tenofovir, or PEGinterferon alfa-2a) are those with HBV DNA >2000 IU/mL and elevated ALT.  Table 6 lists recommendations for those with HBeAg-negative.  Main group needing treatment are the same (HBV DNA >2000 IU/mL and elevated ALT).
  • With both groups (HBe-Ag negative and positive), “consider liver biopsy or transient elastography” if elevated HBV DNA >2000 and normal ALT.  If histologic disease present, consider treatment.
  • One point the authors make about therapy regards duration: “Historically, HBeAg seroconversion was considered a durable response, and discontinuation of antiviral therapy was recommended after a period of consolidation therapy of 6-12 months from the time of HBeAg seroconversion. However, patients who discontinue therapy …can experience recurrent viremia and ALT flares.  Thus, long-term therapy is justified.”
  • For HBeAg negative patients who have compensated liver disease, loss of HBsAg for 6-12 months may be discontinued from therapy.