Page 23 – Practical Gastro

INTRODUCTION

Portal hypertension (PH) is a serious complication of cirrhosis. Survival in cirrhosis is related to the presence of hepatic decompensation, with survival markedly reduced when decompensation occurs. PH is the cause of many of the major complications of liver disease such as ascites, variceal hemorrhage, hepatic encephalopathy, hepatocellular carcinoma and death.

Measurement of the hepatic venous pressure gradient (HVPG) or portal pressure gradient (PPG) accurately reflects the severity of PH. The PPG is the single best prognostic factor in liver disease. As such, PPG can inform and guide medical therapy as well as predict liver decompensation and risk of hepatocellular carcinoma (HCC).A HVPG > 5 mm Hg defines PH. HVPG between 6-9 mm Hg is considered mild PH whereas greater than or equal to 10 mm Hg is considered clinically significant portal hypertension (CSPH). An HVPG > 9 mm Hg predicts cirrhosis.

When the HVPG is greater than or equal to 12 mm Hg, the risk of acute variceal hemorrhage (AVH) is increased. A HVPG greater than or equal to 16 mm Hg is associated with a significantly increased risk of hepatic decompensation (HD) and death. Clinically significant portal hypertension (CSPH) increases risk of early mortality after emergency surgery. In patients with a HVPG >10 mm Hg there is a six-fold increase in the risk of HCC. A HVPG < 10 mm Hg in a patient with compensated cirrhosis is associated with a 90% probability of not developing HD in a median follow up of four years. A HVPG greater than or equal to 20 mm Hg in a patient with compensated cirrhosis independently predicts early and more frequent HD and poorer outcomes, such as failure Figure 1. to control bleeding, early rebleeding, and death during AVH.

For every 1 mm Hg increase in HVPG, there is a 3% increased risk of mortality independent of the patient’s MELD score. For example, a patient with cirrhosis with a HVPG of 15 mm Hg has a 30% higher mortality risk over a patient with HVPG of 5 mm Hg. Moreover, HVPG may be helpful in identifying patients with intermediate MELD scores who should be considered for early liver transplantation due to higher mortality risk than predicted by MELD alone. As such, it is often important to know the actual HVPG in patients with cirrhosis, as it can guide therapy and help predict clinical outcomes.

Traditional Transjugular Hepatic Venous Pressure Gradient Measurement

Interventional radiologists have traditionally performed HVPG measurements by transjugular approach. Under local anesthesia, with or without sedation, a catheter introducer is placed into the right internal jugular vein and, with contrast under fluoroscopic guidance, is advanced into the inferior vena cava (IVC). The balloon is positioned into a large hepatic vein (HV) as confirmed with injection of contrast media. The balloon is inflated, blocking the outflow of the cannulated HV. A transducer is attached to the system. A series of three pressure measurements are obtained of the wedged hepatic venous pressure (WHVP) and free hepatic venous pressure (FHVP). The difference between the WHVP and FHVP is referred to as the hepatic venous pressure gradient (HVPG), a surrogate of portal pressure, though not a direct measurement of PPG.

Using the same venous access, liver biopsy can be performed. Under fluoroscopy a needle introducer sheath is passed into the hepatic vein and a biopsy needle is advanced into the liver parenchyma to obtain an aspiration or core biopsy of liver. Disadvantages of the transjugular approach include patient discomfort from jugular vein puncture, the necessity of exposure to ionizing radiation, and the fact that it is an indirect measurement of portal vein pressure.

Description of EUS PPGM Procedure

An alternative approach to transjugular HVPG measurement is the endoscopic ultrasound (EUS)guided approach to measuring the portal pressure gradient. (Figure 1) The portal pressure gradient measurement (PPGM) is obtained by EUS guided needle puncture through the liver parenchyma into a hepatic vein branch and the portal vein. Direct pressure measurements obtained from the portal vein (PV) and the hepatic vein (HV) can be obtained through the EUS needle utilizing a self-calibrating compact pressure transducer with

integrated digital display (Compass CT, Centurion Medical Products Corp). A Cook EchoTip Insight

25-gauge EUS needle (Cook Endoscopy, Winston Salem NC) with 5.2 French sheath, transducer, and 90 cm non-compressible tubing with stopcock, come prepackaged together.

An esophagogastroduodenoscopy (EGD) is performed first to screen for esophageal varies (EV) and portal hypertensive gastropathy (PHG). This is followed by an EUS exam looking for signs of liver disease such as blunting of the liver edge,

liver nodularity, the presence of ascites and varices not appreciated on the EGD exam or other imaging studies, as well as liver evaluation for the presence of focal liver lesions.

During the EUS exam the endosonographer identifies an optimal HV branch and the PV. HV branches are more proximal. The IVC is easily identified in the cardia region of the stomach. The right hepatic vein (RHV) comes off the IVC first and is seen from the proximal stomach. The MHV branch comes off the IVC confluence with a typical “elephant trunk” appearance, uniform along its length and is often the best branch of the HV to target. The LHV is seen by EUS more distally in the stomach. The hepatic vein branches have a classic pulsatile four phase (multiphase) flow pattern on doppler. The PV has more hyperechoic walls and a monophasic venous “hum” pattern on doppler flow. The umbilical portion of left PV with typical “fish-eye” appearance and the ligamentum teres and ligamentum venosum arising on each side is usually most easily targeted.

Once preliminary EGD and EUS exam have been performed and the decision is made that PPGM can be performed, the Pressure Gradient Measurement System is prepared. During this time, sheer wave elastography (SWE) of the liver can be performed by positioning the probe over the region of interest avoiding vessels and taking an average of 10 measurements. SWE can predict fibrosis. Typically, liver biopsy (EUS-LB) is performed after PPGM.

Once the system is set up with non-compressible tubing flushed with heparinized saline it is attached to the FNA needle. With the patient in supine position, the transducer is gently held by the assistant at the patients left side, generally around axilla and at the level of the patient’s heart. Care should be taken by the assistant to not put any pressure on the back of the syringe during the pressure measurements and maintain the transducer in a stable and consistent level position throughout the procedure.

The liver parenchyma is punctured with the EUS needle and directed into the center of the HV or the PV. Heparinized saline is flushed through the tubing and bubbles observed within the vessel lumen. There is typically a rise or bump in pressure followed by steady drop until a steady Figure 1e. Image of 25g needle in portal vein

state pressure measurement is achieved over one minute. An average of a series of three sequential readings is taken, ignoring any widely discrepant readings.

As the needle is withdrawn out of the liver, doppler flow is used to confirm no bleeding from the needle tract or the surface of the liver. The EUS scope is repositioned to identify the next target vessel. After completing PPGM, EUS-LB can be performed, the left lobe from transgastric approach and if desired the right lobe from transduodenal approach. Liver core samples are expressed onto filter paper or gauze and transferred to a formalin container to send to pathology. We perform

EUS-LB with a 19-gauge FNB needle using wet suction technique using heparinized saline with one pass with 1-3 actuations into one or both lobes of the liver.

Published Results to Date

High success rates for PPG measurement have been achieved with no reports of major adverse events, although data on EUS-PPG measurements are limited at this time. In a multicenter study of 49 patients a 100% success rate was achieved with no major adverse events. Higher mean PPGs were found in patients with clinical portal hypertension including EV, PHG and thrombocytopenia. Patients with PPG > 5 mm Hg were 10 times more likely to have advanced fibrosis on liver histology and 13 times more likely if PPG was >10 mm Hg.

Risk of Adverse Events

EUS-PPGM involves the usual risks of sedated endoscopic exam and EUS-FNA and EUS-LB may be less painful and yield a greater number of portal tracts than percutaneous liver biopsy. EUSLB allows sampling of both lobes of the liver. The risk of adverse events for patients undergoing EUSLB is approximately 2.9%, lower with 19 gauge needle. No major adverse events have been reported with EUS PPGM. Samarasena et al. reported no major early or late adverse events in a series of 76 patients undergoing EUS-PPG measurement and EUS-LB. Mild post procedure pain has been reported following EUS-PPGM and EUS-LB.

Relative contraindications to EUS-PPG include platelet count <50,000, INR >2, antiplatelet therapy, systemic anticoagulation, and large volume ascites that precluded safe needle access to the liver and the hepatic vasculature, although many patients with some degree of ascites can undergo the procedure. Antibiotic prophylaxis is recommended.

Conclusion

EUS-PPGM is a safe, easy, and effective system to assess patients with known or suspected liver disease. Moreover, the “one-stop shop” service to assess for EV and PHG, perform elastography and EUS-LB is attractive and may drive both acceptance and demand.

References

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2006;44(1):217-231. doi:10.1016/j.jhep.2005.10.013}
^{de Franchis R; Baveno V Faculty. Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol. 2010;53(4):762-768. doi:10.1016/j.jhep.2010.06.004}
^{Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J. Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases [published correction appears in Hepatology. 2017 Jul;66(1):304]. Hepatology. 2017;65(1):310-335. doi:10.1002/hep.28906}
^{Perelló A, Escorsell A, Bru C, et al. Wedged hepatic venous pressure adequately reflects portal pressure in hepatitis C virus-related cirrhosis. Hepatology. 1999;30(6):1393-1397. doi:10.1002/hep.510300628}
^{La Mura V, Nicolini A, Tosetti G, Primignani M. Cirrhosis and portal hypertension: The importance of risk stratification, the role of hepatic venous pressure gradient measurement. World J Hepatol. 2015;7(4):688-695. doi:10.4254/wjh.v7.i4.688}
^{Gunarathne LS, Rajapaksha H, Shackel N, Angus PW, Herath CB. Cirrhotic portal hypertension: From pathophysiology to novel therapeutics. World J Gastroenterol. 2020;26(40):6111-6140. doi:10.3748/ wjg.v26.i40.6111}
^{Ferral H, Fimmel CJ, Sonnenberg A, Alonzo MJ, Aquisto TM. Transjugular Liver Biopsy with Hemodynamic Evaluation: Correlation between Hepatic Venous Pressure Gradient and Histologic Diagnosis of Cirrhosis. J Clin Imaging Sci. 2021;11:25.
Published 2021 Apr 26. doi:10.25259/JCIS_233_2020}
^{Garcia-Tsao G, Groszmann RJ, Fisher RL, Conn HO, Atterbury CE, Glickman M. Portal pressure, presence of gastroesophageal varices and variceal bleeding. Hepatology. 1985;5(3):419-424. doi:10.1002/ hep.1840050313}
^{Salman MA, Mansour DA, Balamoun HA, et al. Portal venous pressure as a predictor of mortality in cirrhotic patients undergoing emergency surgery.
Asian J Surg. 2019;42(1):338-342. doi:10.1016/j.
asjsur.2018.09.007}
^{Ripoll C, Groszmann RJ, Garcia-Tsao G, et al. Hepatic venous pressure gradient predicts development of hepatocellular carcinoma independently of severity of cirrhosis. J Hepatol. 2009;50(5):923-928.
doi:10.1016/j.jhep.2009.01.014}
^{Ripoll C, Groszmann R, Garcia-Tsao G, et al. Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology. 2007;133(2):481-488.
doi:10.1053/j.gastro.2007.05.024}
^{Jindal A, Bhardwaj A, Kumar G, Sarin SK. Clinical Decompensation and Outcomes in Patients With Compensated Cirrhosis and a Hepatic Venous Pressure Gradient ≥20 mm Hg. Am J
Gastroenterol. 2020;115(10):1624-1633. doi:10.14309/ ajg.0000000000000653}
^{Ripoll C, Bañares R, Rincón D, et al. Influence of hepatic venous pressure gradient on the prediction of survival of patients with cirrhosis in the MELD Era. Hepatology. 2005;42(4):793-801. doi:10.1002/ hep.20871}
^{Kim TY, Suk KT, Jeong SW, et al. The New Cutoff Value of the Hepatic Venous Pressure Gradient on Predicting Long-Term Survival in Cirrhotic Patients. J Korean Med Sci. 2019;34(33):e223. Published 2019 Aug 26. doi:10.3346/jkms.2019.34.e223}
^{Reiberger T, Schwabl P, Trauner M, Peck-Radosavljevic M, Mandorfer M. Measurement of the Hepatic Venous Pressure Gradient and Transjugular Liver Biopsy. J Vis Exp. 2020;(160):10.3791/58819. Published 2020 Jun 18. doi:10.3791/58819}
^{Ferral H, Fimmel CJ, Sonnenberg A, Alonzo MJ, Aquisto TM. Transjugular Liver Biopsy with Hemodynamic Evaluation: Correlation between Hepatic Venous Pressure Gradient and Histologic Diagnosis of Cirrhosis. J Clin Imaging Sci. 2021;11:25.
Published 2021 Apr 26. doi:10.25259/JCIS_233_2020}
^{Samarasena JB, Chang KJ. Endoscopic UltrasoundGuided Portal Pressure Measurement and Interventions. Clin Endosc. 2018;51(3):222-228. doi:10.5946/ ce.2018.079}
^{Huang JY, Samarasena JB, Tsujino T, et al. EUSguided portal pressure gradient measurement with a simple novel device: a human pilot study. Gastrointest Endosc. 2017;85(5):996-1001. doi:10.1016/j. gie.2016.09.026}
^{Brattain LJ, Telfer BA, Dhyani M, Grajo JR, Samir AE. Objective Liver Fibrosis Estimation from Shear Wave Elastography. Annu Int Conf IEEE Eng Med Biol Soc. 2018;2018:1-5. doi:10.1109/EMBC.2018.8513011}
^{EUS-guided portal pressure gradient measurement in patients with acute or subacute portal hypertension Zhang, Wei et al. Gastrointestinal Endoscopy, Volume 93, Issue 3, 565 – 572}
^{Ali AH, Panchal S, Rao DS, et al. The efficacy and safety of endoscopic ultrasound-guided liver biopsy versus percutaneous liver biopsy in patients with chronic liver disease: a retrospective single-center study. J Ultrasound. 2020;23(2):157-167. doi:10.1007/ s40477-020-00436-z}
^{Diehl DL. Endoscopic Ultrasound-guided Liver Biopsy. Gastrointest Endosc Clin N Am. 2019;29(2):173-186. doi:10.1016/j.giec.2018.11.002}
^{Mohan BP, Shakhatreh M, Garg R, Ponnada S, Adler DG. Efficacy and safety of EUS-guided liver biopsy: a systematic review and meta-analysis. Gastrointest Endosc. 2019 Feb;89(2):238-246.e3. doi: 10.1016/j. gie.2018.10.018. Epub 2018 Oct 31. PMID: 30389469.}
^{EUS-GUIDED PORTAL PRESSURE GRADIENT MEASUREMENT SAFELY PERFORMED WITH EUS-GUIDED LIVER BIOPSY: ENDOHEPATOLOGY IN PRACTICE Samarasena, Jason et al. Gastrointestinal Endoscopy, Volume 91, Issue 6, AB268 – AB269}
^{Portal pressure measurement: Have we come full circle? Bazarbashi, Ahmad Najdat et al. Gastrointestinal Endoscopy, Volume 93, Issue 3, 573 – 576}

NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #216

PEG or PEG Button Replacement: Willy-Nilly or Evidence-Based?

Merin Kinikini,

John C. Fang

The percutaneous endoscopic gastrostomy (PEG) is the most common enteral feeding tube for long term nutrition support. Multiple guidelines and teaching materials are available for initial PEG placement. While this is beneficial for PEG placement, there is little evidence-based published literature to guide clinicians for PEG replacement. Rather than a “Willy-Nilly” approach, herein we combine the available evidence, published guidelines and expert opinion on PEG replacement. We review the why, when, what, who, and how of replacing PEGs with emphasis on practical clinical guidance. Optimal management of patients with PEG tubes necessarily requires expert PEG replacement practices to provide the best quality of life for these patients.

INTRODUCTION

Initial percutaneous endoscopic gastrostomy Although this review focuses on replacement of (PEG) placement is a commonly performed percutaneous gastrostomies placed endoscopically, procedure for patients unable to maintain the information is also applicable for percutaneous nutrition with adequate oral intake and there are multiple professional society guidelines for its use. Approximately 200,000 initial PEG tube placements are performed in the U.S. annually. With such a large number of PEG tubes being placed, correspondingly there are a large number of PEG tubes being replaced as well. Despite this, there are no official recommendations for the replacement of PEG tubes. Appropriate timing, technique and management of PEG replacement is critical to prevent complications and provide maximal benefit of long-term enteral feeding.

Although this review focuses on replacement of percutaneous gastrostomies placed endoscopically, the information is also applicable for percutaneous gastrostomies placed radiographically as well. In this article we will review the why, when, what, who, and how of PEG replacement based on both expert opinion and available published evidence.^1-3

The WHY of PEG Replacement

The “Why” of PEG replacement can be divided into scheduled vs. unscheduled PEG replacement. Scheduled replacement occurs when the PEG is replaced before any significant deterioration or complication resulting in malfunction of the existing PEG has occurred. Scheduled PEG replacement is the preferred and most common form of PEG replacement (Table 1).

Unscheduled PEG replacement occurs when PEG malfunction due to either deterioration of the PEG and/or if complications have occurred (Table 1). Symptoms of PEG malfunction requiring replacement include: inability to infuse formula/ water or medications, peristomal leakage, severe leakage or backflow from the tube itself, and tube displacement. Tube deterioration consists of retention balloon breakage or leakage, valve incompetence on low profile tubes and tube cracking from aging and/or fungal colonization. Complications requiring replacement include: buried bumper syndrome, gastric outlet obstruction from internal bumper migrating and lodging in the pylorus, and severe stoma site pain or unresolving infection despite antibiotics.4 Buried bumper syndrome occurs when there is too much pressure between the internal and external bumper and the internal bumper migrates into the stoma tract.

The WHEN of PEG Replacement

The “When” in PEG replacement encompasses when it is safe to replace a PEG tube after initial placement and also how long an existing tube will function before deterioration resulting in malfunction occurs. After initial placement the PEG stoma tract begins to mature in 1-2 weeks and is usually well-formed in 4 weeks (Figure 1,2). This process may take longer in patients with impaired wound healing (ascites, malnutrition, immunosuppressive medications or states, diabetes, obesity). Therefore, PEG replacement after initial placement can be safely performed as soon as 4-6 weeks in most patients. It may need to be longer (up to 3 months) in higher risk patients as described above.⁵ If a tube is inadvertently removed or has a complication requiring replacement before stoma tract maturation, confirmation of correct placement with one of the methods explained later in this article in the “How” of PEG placement is mandatory.³

The directions for use for replacement intervals from the commercial manufacturers in the U.S. vary, but in general ranges are 6-12 months for non-balloon tubes and 3-6 months for balloon tubes. Balloon tubes have inflatable balloons that function as the internal bumper while nonballoon tubes have an internal bumper made of solid silicone rubber in various shapes. Published data demonstrate that non-balloon tubes may function for up to 2 years.² The goal is for patients to have PEG replacements on a scheduled basis (vs. unscheduled), before tube breakage or malfunction/ complications occur, although there are no studies comparing scheduled vs. unscheduled replacement strategies. It is the authors’ practice to plan for PEG replacement near the end of predicted life of tube (i.e. ~ 12 months for non-balloon and 4-5 months for balloon tubes). We also often prescribe an additional PEG replacement tube (or even a red rubber catheter) for patients to have available at home for balloon tubes in case of balloon breakage or any other event that may result in dislodgement before scheduled replacement. Weekly checking of water volume has also been shown to decrease dislodgement from balloon breakage.²

The WHAT of PEG Replacement

The “What” in PEG replacement is deciding on a solid (non-balloon) vs. balloon internal bolster and standard vs. low profile external configuration. The overriding principle is what is best for the patient and their caregivers in terms of convenience

and functionality. A solid internal bolster will last up to twice as long as a balloon internal bolster tube (i.e., 12 months vs. 6 months). However, replacing a solid tube is more complicated as they are removed and replaced using traction (sometimes using a metal obturator with the lowprofile non-balloon tubes) involving significant force. This can cause significant pain for the patient and generally performed by a health care professional. Balloon tubes are deflated on removal and inflated on replacement non-traumatically and can be performed by the patient or caregiver in the home setting. Finally, if a patient is on palliative care/hospice, a non-balloon tube with its greater longevity may be preferred so the tube will last the lifetime of the patient. The decision on a standard tube vs. a lowprofile tube is dependent on what the tube is being used for. If the tube is being used for drainage, then a standard profile tube is preferred since it does not have the anti-reflux valve that low profile tubes have. If the tube is used for infusion or feeding,

then factors to weigh include the size of the tube and the dexterity and body habitus of the patient. If the patient is interested in having a low-profile feeding tube then they, or their caregivers, must have greater dexterity to be able to manipulate the feeding tube connectors. A more active or younger patient may prefer a low-profile tube for lifestyle and cosmetic reasons. Commercially available PEG replacement tubes come in various combinations of standard vs. low profile with non-balloon vs. balloon internal bolsters in various length/ diameter combinations. The appropriate specific combination of external configuration, internal bolster type, and size/length can greatly improve function and quality of life for patients requiring PEG tubes. Generally, standard profile PEG tubes are placed initially and then can be replaced by low profile tubes at the first replacement or once the tract is matured.⁴

The WHO of PEG Replacement

The “Who” to replace PEG tubes include the patients themselves, family/caregivers, and health care professionals. Health care professionals include dietitians, nurses, advanced practice clinicians and physicians (interventional radiologists, surgeons and gastroenterologists). Patients, family members/ caregivers and nurses generally exchange balloon type tubes given their overall ease and safety. The pediatric community has pioneered family members and caregivers performing home tube replacement. Traditionally, the initial tube change is performed by a highly skilled provider in the clinic or other outpatient setting in which the parents/caregivers (or adult patients) are taught and then observed on the correct replacement technique. Additional teaching aids include training dolls/bears, manufacturer and “YouTube” “how to” videos (www.youtube.com/watch?v=maJaKMqIVQg, www.youtube/Zi8OMxqYEO8). When performing home PEG replacement, if there is any concern for misplacement then patients are instructed to contact their health care professional or if unavailable go to the emergency department to have a more definitive confirmation method performed. The patient should be evaluated at least yearly to assure the tube and the tube site both look appropriate. Specialty trained physicians, or advanced practice clinicians, also perform standard scheduled replacements and are

required for unscheduled replacements. Appropriately trained non-physicians (i.e. nurses) or patients, can safely and far more economically replace established PEG tubes in the home setting.

The HOW of PEG Replacement

As noted previously, there are no guidelines for the “how” to replace PEG tubes, but the general principles include:

a well-formed mature stoma tract
good control and appropriate direction of force during replacement, and
appropriate confirmation of intra-gastric tube position if there are any concerns for misplacement.⁵

Scheduled replacements require no antibiotics and the tubes can be used immediately as long as no complications are suspected. Stoma tract measurement is required when initially replacing with a low-profile tube and can be estimated from the markings and fit of the existing tube. Dedicated stoma tract measuring devices will give more accurate measurements, remembering that the tract length may increase 0.5-1.0 cm when the patient goes from supine to upright position.⁶

Specific manufacturer’s directions for use should always be followed. There is good evidence that percutaneous removal and replacement of PEG tubes is safe and significantly more cost-effective than endoscopic or fluoroscopic methods as long as proper technique, protocols and training are employed.^7-9 Replacing existing balloon type PEG tubes are the most straightforward and least likely to develop complications. These tubes will have a port labeled balloon or “bal” if unsure of the type of internal bolster. Ensure that all the necessary supplies are immediately available (Table 2). The exact size (diameter in French and length) tube can be ordered ahead of time for the procedure if replacing with the same size tube. If replacing standard profile tube with low profile tube, the length can be estimated by noting the markings on the existing tube of where it exits the skin when the patient is in the upright position.⁶ Viscous lidocaine is applied at the site and on the new tube as a lubricant. The balloon port is accessed with a slip tip syringe and the water is completely removed. The tube is then removed using a gentle traction on withdrawal. There may be a little resistance where the deflated balloon exits the skin, but there should not be significant resistance to removal. In some cases, there will be gastric fluid, air or formula that may leak from the stoma. The stoma tract can now be measured if there is concern that a different length tube will be required. The lubricated new replacement balloon tube can then be inserted into the tract with gentle force in the direction of the stoma tract. The practitioner will often feel a mild “pop” when the ridge of the deflated balloon enters into the gastric lumen (Figure 3). The balloon is then inflated with the recommended amount of water (from 4-10 mL). The tube should then be pulled until it meets resistance to ensure balloon retention of the tube. The tube can then be aspirated to check for gastric fluid return, though this does not absolutely guarantee appropriate placement and gastric fluid return does not always occur despite appropriate placement. It is optional whether patients should be fasting before the procedure; patients not fasted may have more retained gastric fluids or formula. The tube should then easily flush with water and spin in the tract. The external bolster should have 0.5-1.0 mm of distance between the bolster and the skin. The site can then be dressed with a small amount of gauze dressing (i.e., one-two 2×2 or 4×4 pads) or no dressing if the site is not prone to leakage.⁴ As mentioned previously, once observed, this can be completed by patient or lay caregiver.

Non-balloon PEG tubes can also be replaced percutaneously without endoscopy, though more training is required and replacement can cause more discomfort and pain. Therefore, non-balloon replacements are not performed by patients or lay caregivers. Given this kind of PEG replacement, health care providers may elect to use mild to moderate sedation for the procedure. All present commercially available non-balloon tubes have soft, deformable internal bolsters that allow traction removal. The external bolster or tube is grasped tightly close to where it exits the skin and the PEG tube is pulled using firm traction while placing fingers on either side of the tube against the skin. The tube should pop through the abdominal wall with moderate pulling force. Some manufacturers include a metal obturator to help deform and slim the profile of the internal bolster allowing for less traumatic removal. The cut and push method is used less often in which the external portion of the tube is cut and remaining tube is pushed into the gastric lumen. Then the cut internal bolster end is either allowed to pass through the gastrointestinal (GI) tract or is retrieved endoscopically using forceps, snare or basket if there is concern for obstruction distally. This scenario also occurs if the internal bolster breaks off during attempted traction removal. There may be some bleeding and/ or gastric fluid leakage at the site. Replacement with a balloon tube then proceeds as above. If a new non-balloon tube is chosen for replacement, an obturator is again used to deform the internal bolster and again the practitioner will often feel a “pop” when the deformed internal bolster enters the gastric lumen (Figure 4a and 4b). There is a non-balloon option that uses a biodegradable capsule (Applied Medical Technologies, Inc. www. appliedmedical.net) to constrain the internal bolster that is released once deployed inside the gastric lumen (Figure 5a and 5b). Checking for internal bolster retention, aspiration, and flushing proceeds as described earlier. Confirmation of correct intra-gastric replacement is not required for all PEG replacements although there have been no studies comparing confirmation vs. non-confirmation. The overriding principle is to confirm placement by endoscopic or radiographic means if there is any concern for inadequate stoma tract maturation or misplacement. This may include unusual pain with tube placement, the replacement tube did not go in easily as expected or if the tube doesn’t flush and aspirate gastric contents easily. Auscultation of injected air or aspiration of gastric contents are not 100% reliable forms of confirmation, but visualization of gastric contents is commonly used with bedside placement. The “blue sky” and air insufflation methods have been reported to confirm correct replacement. In the blue-sky method, grape juice (originally methylene blue) is infused then witnessed to be aspirated using a syringe. In the air insufflation method, 240 mL of air is injected with abdominal radiograph after insufflation demonstrating the tube clearly seen in the distended stomach. Visualization at endoscopy or radiographically by infusion of gastrograffin (i.e., “tubogram”) are the most reliable methods of confirmation. However, they are also the most costly and inconvenient.³

The most feared complication of tube replacement is tract disruption with misplacement into the peritoneum. If recognized early, attempts may be made to remove and reposition the tube under endoscopic or fluoroscopic guidance. However, in most cases removal of the misplaced tube, antibiotic administration, and allowing the stoma site to heal is the best course of action. A nasoenteric tube can be used until stoma tract healing has occurred and a new PEG placed later.

However, if frank peritonitis develops, an urgent surgical consult is warranted.

Misplacement into the colon can also occur. In this situation the initial PEG has been placed through the transverse colon into stomach. Often the initial PEG will function well, but upon exchange the replacement PEG is placed into the colon. Symptoms include pain, infection, feculent leakage, and diarrhea. Treatment is removing the misplaced PEG, waiting for the stoma tract to heal and placement of new PEG.¹⁰ Other complications of PEG replacement include bleeding, pain, infection, and peristomal leakage. Peristomal leakage occurs more often in those with underlying medical conditions that predispose them to delayed wound healing. It is important to evaluate for other causes, such as tube displacement, buried bumper, and delayed gastric emptying. It is also important to minimize sideto-side movement of the PEG tube where it exits the skin as that can enlarge the tract. This can be accomplished by changing to low profile tube or external stabilization with a right-angle bumper or clamp. Good stoma care with zinc oxide-based protectants and consult to wound

ostomy care are also useful. Prokinetics and proton pump inhibitor use may decrease gastric fluid volume. It is not usually helpful to put a larger tube in the tract, as that will eventually result in a larger stoma with increased leakage. If the tract is mature, one can place a wire through the tract and remove the existing tube for 24-48 hours to allow the stoma tract to partially close. Then another tube is replaced into the tract using wire guidance.^2,4 Situations involving PEG replacement that deserve special mention are dislodgement, which can result in buried bumper or complete removal if tubes are dislodged externally, and obstruction, if the tube dislodges or migrates internally. PEG dislodgment with complete removal of the tube before tract maturation must be addressed urgently. If the gastric wall has not adhered to the abdominal wall, peritonitis can occur. Replacement can be attempted endoscopically or radiographically by experienced physicians. Failing that, the patient may require emergent surgical revision, washout, and intravenous antibiotics. If the clinician is unsure of tract maturation, the standard methods above for tube replacement may be used with endoscopic or radiologic confirmation of correct tube position.

Buried bumper syndrome occurs when the internal bumper migrates into the stoma tract and is much less likely to occur with balloon tubes. Multiple methods have been described endoscopically to manipulate the buried bumper back into the gastric lumen, but often the simplest method is to remove the buried tube and place a new tube into the existing tract using the pull method. If the tube migrates internally, the internal bumper can lodge and obstruct the pylorus. Once recognized, the tube can usually just be pulled back and the PRACTICAL GASTROENTEROLOGY • NOVEMBER 2021 external bolster reset appropriately. The way to prevent both of these issues is to know, document, and regularly monitor the external bolster position. Other preventative recommendations include rotating the tube daily and pushing the tube in and out ~ 2 cm weekly after stoma tract maturation.²

CONCLUSIONS

PEG replacement is a critical component of enteral access, but there is very limited published data and guidance on its practice. Multiple caregivers including patients, families, and healthcare professionals at all levels may be involved and care from multi-disciplinary teams are required for management of patients requiring PEG tubes. We prefer timely replacement of PEG tubes using appropriate protocols and the techniques described above. Awareness of the data and expert opinion are required to prevent, perform, and manage complications from PEG replacement. This will allow provision of optimal nutritional, hydration, and medication support as well as maximize quality of life for patients living with PEG tubes.

References

^{Boullata J, Carrera A, Harvey L, et al. ASPEN Safe Practices for Enteral Nutrition Therapy. JPEN J Parenter Enteral Nutr. 2017;41(1):15-103.}
^{Gkolfakis P, Arvanitakis M, Despott EJ, et al. Endoscopic management of enteral tubes in adult patients – Part 2: Peri- and postprocedural management. European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. 2021;53(2):178-195.}
^{Bischoff SC, Austin P, Boeykens K. et al. ESPEN guideline on home enteral nutrition. Clin Nutr. 2020;39(1):5-22.}
^{Lord L. Enteral Access Devices: Types, Function, Care and Challenges. Nutr Clin Pract. 2018;33(1):16-38.}
^{Lohsiriwat V. Percutaneous endoscopic gastrostomy tube replacement: A simple procedure? World J of Gastrointest Endosc. 2013;5(1):14-8.}
^{Steenblik M, Hilden K, Fang JC. A retrospective correlation of percutaneous feeding tube stoma length in sitting and supine positions compared with body mass index. Nutr Clin Pract. 2012;27(3):406-9.}
^{Khoury T, Daher S, Yaari S, et al. To Pull or to Scope: A Prospective Safety and Cost-effectiveness of Percutaneous Endoscopic Gastrostomy Tube Replacement Methods. J Clin Gastroenterol. 2019;53(1):e37-e40.}
^{Lee C, Kang H, Lim Y, et al. Comparison of complications between endoscopic and percutaneous replacement of percutaneous endoscopic gastrostomy tubes. J Korean Med Sci. 2013;28(12):1781-7.}
^{Rahnemai-Azar A, Rahnemaiazar A, Naghshizadian R, et al. Percutaneous endoscopic gastrostomy: Indications, technique, complications and management. World J of Gastroenterol. 2014;20(24):7739-51.}
^{Blumenstein I, Shastri Y, and Stein J. Gastroenteric tube feeding: techniques, problems and solutions. World J of Gastroenterol. 2014;20(26):8505-24.}

MEDICAL BULLETIN BOARD

Redhill Biopharma’s Talicia Added to Medical Contract Drug List with No Prior Authorization Requirements

Addition of Talicia^®by Medi-Cal Fee-For-Service (FFS) Contract Drug List (CDL) with no prior authorization is an important expansion of coverage for California patients and continues to increase Talicia’s overall unrestricted coverage

Coverage commenced for two million patients in MediCal’s FFS plan on October 1st, 2021

Talicia^®is the first and only FDA-approved rifabutinbased therapy for H. pylori infection, designed as a first-line option to address the high resistance of H. pylori bacteria to standard-of-care therapies H. pylori bacterial infection is a Group 1 carcinogen and the strongest risk factor for gastric cancer; H. pylori affects approximately 35% of the U.S. population

TEL-AVIV, Israel and RALEIGH, N.C., October 6, 2021, RedHill Biopharma Ltd. (Nasdaq: RDHL) (“RedHill” or the “Company”), a specialty biopharmaceutical company, today announced that Medi-Cal – California’s Medicaid Health Care program covering two million patients – has added Talicia^® (omeprazole magnesium, amoxicillin and rifabutin)[1] to its Contract Drug List (CDL) for H. pylori treatment, with no prior authorization required, effective October 1, 2021.

Coverage for Talicia commenced for two million patients in Medi-Cal’s California FFS plan on October 1, 2021.

“Medi-Cal’s addition of Talicia with no prior authorization required is an important step in Talicia’s continuing growth and we are pleased that it will be made available to Medi-Cal’s 2 million FFS lives,” said Rick Scruggs, RedHill’s Chief Commercial Officer. “There is growing recognition of the need to employ effective, first-line therapy against H. pylori infections that does not rely on clarithromycin and that patients can tolerate well and adhere to over 14 days of therapy. Talicia meets those criteria.”

About Talicia^®

Talicia^® is the only rifabutin-based therapy approved for the treatment of H. pylori infection and is designed to address the high resistance of H. pylori bacteria to clarithromycin-based therapies. The high rates of H. pylori resistance to clarithromycin have led to significant rates of treatment failure with clarithromycin-based therapies and are a strong public health concern, as highlighted by the FDA and the World Health Organization (WHO) in recent years.

Talicia^® is a novel, fixed-dose, all-in-one oral capsule combination of two antibiotics (amoxicillin and rifabutin) and a proton pump inhibitor (PPI) (omeprazole). In November 2019, Talicia^® was approved by the U.S. FDA for the treatment of H. pylori infection in adults. In the pivotal Phase 3 study, Talicia^® demonstrated 84% eradication of H. pylori infection in the intent-to-treat (ITT) group vs. 58% in the active comparator arm (p<0.0001). Minimal to zero resistance to rifabutin, a key component of Talicia^®, was detected in RedHill’s pivotal Phase 3 study. Further, in

an analysis of data from this study, it was observed that subjects who were confirmed adherent[ii] to their therapy had response rates of 90.3% in the Talicia^® arm vs. 64.7% in the active comparator arm[iii].

Talicia^® is eligible for a total of eight years of U.S. market exclusivity under its Qualified Infectious Disease Product (QIDP) designation and is also covered by U.S. patents which extend patent protection until 2034 with additional patents and applications pending and granted in various territories worldwide.

About H. pylori

H. pylori is a bacterial infection that affects approximately 35%[iv] of the U.S. population, with an estimated two million patients treated annually[v]. Worldwide, more than 50% of the population has H. pylori infection, which is classified by the WHO as a Group 1 carcinogen. It remains the strongest known risk factor for gastric cancer[vi] and a major risk factor for peptic ulcer disease[vii] and gastric mucosa-associated lymphoid tissue (MALT) lymphoma[viii]. More than 27,000 Americans are diagnosed with gastric cancer annually[ix]. Eradication of H. pylori is becoming increasingly difficult, with current therapies failing in approximately 25-40% of patients who remain H. pylori-positive due to high resistance of H. pylori to antibiotics commonly used in standard combination therapies[x].

About RedHill Biopharma

RedHill Biopharma Ltd. (Nasdaq: RDHL) is a specialty biopharmaceutical company primarily focused on gastrointestinal and infectious diseases. RedHill promotes the gastrointestinal drugs, Movantik^® for opioid-induced constipation in adults[xi], Talicia^® for the treatment of Helicobacter pylori (H. pylori) infection in adults[xii], and Aemcolo^® for the treatment of travelers’ diarrhea in adults[xiii]. RedHill’s key clinical late-stage development programs include: (i) RHB-204, with an ongoing Phase 3 study for pulmonary nontuberculous mycobacteria (NTM) disease; (ii) opaganib (ABC294640), a first-in-class oral SK2

selective inhibitor targeting multiple indications with a Phase 2/3 program for COVID-19 and Phase 2 studies for prostate cancer and cholangiocarcinoma ongoing; (iii) RHB-107 (upamostat), an oral serine protease inhibitor in a U.S. Phase 2/3 study as treatment for symptomatic COVID-19, and targeting multiple other cancer and inflammatory gastrointestinal diseases; (iv) RHB-104, with positive results from a first Phase 3 study for Crohn’s disease; (v) RHB-102 , with positive results from a Phase 3 study for acute gastroenteritis and gastritis and positive results from a Phase 2 study for IBS-D; and (vi) RHB-106, an encapsulated bowel preparation.

More information about the Company is available at: redhillbio.com

INDICATION AND USAGE

Talicia is a three-drug combination of omeprazole, a proton pump inhibitor, amoxicillin, a penicillin-class antibacterial, and rifabutin, a rifamycin antibacterial, indicated for the treatment of Helicobacter pylori infection in adults.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Talicia and other antibacterial drugs, Talicia should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

IMPORTANT SAFETY INFORMATION

Talicia contains omeprazole, a proton pump inhibitor (PPI), amoxicillin, a penicillin-class antibacterial and rifabutin, a rifamycin antibacterial. It is contraindicated in patients with known hypersensitivity to any of these medications, any other components of the formulation, any other beta-lactams or any other rifamycin.

Talicia is contraindicated in patients receiving rilpivirine-containing products.

Talicia is contraindicated in patients receiving delavirdine or voriconazole.

Serious and occasionally fatal hypersensitivity reactions have been reported with omeprazole, amoxicillin and rifabutin.

Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents and may range from mild diarrhea to fatal colitis.

Talicia may cause fetal harm. Talicia is not recommended for use in pregnancy.

Talicia may reduce the efficacy of hormonal

contraceptives. An additional non-hormonal method of contraception is recommended when taking Talicia.

Talicia should not be used in patients with hepatic impairment or severe renal impairment.

Acute Interstitial Nephritis has been observed in patients taking PPIs and penicillins.

Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs. These events have occurred as both new onset and exacerbation of existing autoimmune disease.

The most common adverse reactions (≥1%) were diarrhea, headache, nausea, abdominal pain, chromaturia, rash, dyspepsia, oropharyngeal pain, vomiting, and vulvovaginal candidiasis.

To report SUSPECTED ADVERSE REACTIONS, contact RedHill Biopharma INC. at:

1-833-ADRHILL (1-833-237-4455) or FDA at: 1-800-FDA-1088 or www.fda.gov/medwatch

Full prescribing information for Talicia is available at: Talicia.com

Talicia^® (omeprazole magnesium, amoxicillin and rifabutin) delayed-release capsules 10 mg/250 mg/12.5 mg is indicated for the treatment of Helicobacter pylori (H. pylori) infection in adults. For full prescribing information see: www.Talicia.com.
Defined as the PK population which included those subjects in the ITT population who had demonstrated presence of any component of investigational drug at visit 3 (approx. day 13) or had undetected levels drawn >250 hours after the last dose.
The pivotal Phase 3 study with Talicia^® demonstrated 84% eradication of H. pylori infection with Talicia^® vs. 58% in the active comparator arm (ITT analysis, p<0.0001).
Hooi JKY et al. Global Prevalence of Helicobacter pylori Infection: Systematic Review and Meta-Analysis. Gastroenterology 2017; 153:420-429.
IQVIA Custom Study for RedHill Biopharma, 2019
Lamb A et al. Role of the Helicobacter pylori-Induced inflammatory response in the development of gastric cancer. J Cell Biochem 2013;114.3:491-497.
NIH – Helicobacter pylori and Cancer, September 2013.
Hu Q et al. Gastric mucosa-associated lymphoid tissue lymphoma and Helicobacter pylori infection: a review of current diagnosis and management. Biomarker research 2016;4.1:15.
National Cancer Institute, Surveillance, Epidemiology, and End Results Program (SEER).
Malfertheiner P. et al. Management of Helicobacter pylori infection – the Maastricht IV/ Florence Consensus Report, Gut 2012;61:646-664; O’Connor A. et al. Treatment of Helicobacter pylori Infection 2015, Helicobacter 20 (S1) 54-61; Venerito M. et al. Meta-analysis of bismuth quadruple therapy versus clarithromycin triple therapy for empiric primary treatment of Helicobacter pylori infection. Digestion 2013;88(1):33-45.
Full prescribing information for Movantik^® (naloxegol) is available at: www.Movantik.com.
Full prescribing information for Talicia^® (omeprazole magnesium, amoxicillin and rifabutin) is available at: www.Talicia. com.
Full prescribing information for Aemcolo^® (rifamycin) is available at: www.Aemcolo.com.

MEDICAL BULLETIN BOARD

VISBIOME® – HIGH POTENCY PROBIOTIC

Visbiome is intended for the dietary management of dysbiosis associated with irritable bowel syndrome (IBS), ulcerative colitis (UC), antibiotic-associated diarrhea (AAD), pouchitis and hepatic encephalopathy (HE).

Visbiome is a medical food, non-drug therapy, that addresses distinct nutritional requirements which promote microbial balance that cannot be addressed by modifying the diet alone. Visbiome is a unique blend of 8 strains of bacteria, a formulation with more than 75 clinical trials, and more than 20 years of research, making it the most studied multi-strain probiotic formulation on the market. The product is made in the USA, available in capsule or powder format, and shipped cold with temperature monitoring sensors.

Q: Is Visbiome^® the most studied multi-strain probiotic?

A: Yes, Visbiome, a probiotic medical food, has been the subject of over 75 peer reviewed clinical studies, the most of any multi-strain probiotic. There have been 10 studies in the dietary management of irritable bowel syndrome (IBS) and eight studies in the dietary management of ulcerative colitis (UC). The studies included both adults and children and consisted of more than 500 subjects for each condition.

Q: Is Visbiome^® effective in the management of IBS?

A: Yes, in studies for the dietary management of IBS, Visbiome showed significant relief of symptoms associated with IBS, such as abdominal bloating, pain/discomfort and flatulence, and it was well tolerated.^1,2,3 In one study of children with IBS (4 to 18 years of age), Visbiome was superior to placebo in the primary endpoint of subjective assessment of relief of symptoms.³ Visbiome has also been studied in patients utilizing the low-FODMAP diet for management of IBS symptoms. In this placebo-controlled study, patients on the low-FODMAP diet exhibited a reduced level of Bifidobacterium species suggesting a level of dysbiosis caused by the diet itself. Patients who were co-administered Visbiome with the low-FODMAP diet maintained levels of Bifidobacterium consistent with controls.⁴

Bifidobacterium species are part of the normal inhabitants of a healthy gut and have certain immunomodulatory effects; alterations of Bifidobacterium species have been linked to IBS and other gastrointestinal diseases.^4,5

Q: How does Visbiome^®help in the management of UC?

A: In the dietary management of UC, Visbiome taken in conjunction with conventional therapies has been shown to be beneficial in patients with mild-to-moderate UC.^6,7 Visbiome also has been associated with a decrease in rectal bleeding, and demonstrated a reduction of up to 50% in UC disease activity index (UCDAI) scores, when used as a medical food.⁸ Q: What factors should be considered when recommending a Probiotic for IBS and UC patients?

A: There are certain factors a clinician should consider when recommending a probiotic to a patient:

Recommend probiotics that contain the exact strain and species that have proven patient benefits in peer reviewed clinical studies, and do not extrapolate the success of one probiotic species to another. Some companies cite clinical data on other probiotic products and imply that parallel results can be expected simply because similar species are present, but they have not performed research on their specific formulation.
Consider probiotics that contain a large enough number of viable microorganisms for the conditions.
Consider probiotics from companies that implement procedures in the supply chain to protect the bacteria strains from harmful factors like heat and humidity, so the bacteria remain viable when they arrive to the patient.⁹

References

^{Kim et al. Neurogastro Motil 2005;17:1-10.}
^{Kim et al. Aliment Pharmacol Ther 2003;17:895-904.}
^{Guandalini et al. JPGN. 2010;51:24-30.}
^{Staudacher H, et al. Gastroenterology 2017; 153:936-947.}
^{Tojo R, et al. World J Gastroenterol 2014;20(41).}
^{Sood A, et al. Clin Gastroenterol Hepatol 2009;11:1202-1209.}
^{Miele E, et al. Am J Gastroenterol 2009;104:437-443.}
^{Tursi A, et al. Med Sci Monit (2004); 10(11): PI126-131.}
^{Cong D, et al. World J Gastroenterol 2013;19(36):5973-5980.}

ExeGi Pharma,LLC, Makers of Visbiome^®

For more information, email or call: info@exegipharma.com

(844) 348-4887

FROM THE PEDIATRIC LITERATURE

Determining Genetic Variants in Pediatric Acute Liver Failure

A large number of pediatric acute liver failure (ALF) cases occur with no diagnosed etiology, and there is concern that potential genetic mutations affecting outcome may be present in such patients. Techniques such as next generation sequencing (typically defined as fast massively parallel sequencing) can determine a human genome in less than one day, and the authors of this study looked at the capacity of such screening techniques to determine genetic causes of ALF in children. This retrospective study of pediatric patients seen in a tertiary pediatric hospital in London looked at all cases of ALF over an 18year period in which stored blood was available. Included study patients had no evidence of chronic liver disease. Additionally, such patients needed to have laboratory evidence of ALF defined as having an international normalized ration (INR) ≥ 1.5 not corrected by Vitamin K with associated hepatic encephalopathy or having an INR ≥ 2 with or without hepatic encephalopathy. Clinical characteristics were obtained for all patients, and children with ALF were determined to have an indeterminate cause of disease if no known cause of ALF could be found. Additionally, blood samples underwent next generation sequencing to evaluate for 64 mutations causing genetic and metabolic liver disease in children, exome sequencing to evaluate the entire genome of the affected child and unaffected parents, or sequence variant filtration to determine potential disease-causing variants.

Next generation sequencing occurred in 41 patients while 4 patients underwent exome sequencing. Next generation sequencing identified eight children with either heterozygous or homozygous ALF-causing mutations of NBAS, TWINK, CPT1A, MPV17, DLD, POLG, and SUCLG1. Exome sequencing found mutations in all four children including mutations in LARS1, FAH1, NPC1, and DLD. Interestingly, those children with biallelic variants of such mutations presented with ALF at a significantly younger age and were significantly more likely to die from liver failure. Thus, this study shows that using genetic testing to diagnose unknown causes of ALF in children is beneficial in elucidating primary causes of hepatic disease. This aspect is especially important since liver transplantation for mitochondrial DNA mutations is controversial depending on the mutation as other organs besides the liver can be affected. This study shows that sequencing the genome for pediatric ALF is important to determine causality and outcome, and more work is urgently needed to make such testing easily available and affordable.

Hegarty R, Gibson P, Sambrotta M, Strautnieks S, Foskett P, Ellard S, Baptista J, Lillis S, Bansal S, Vara R, Dhawan A, Grammatikopoulos T, Thompson R. Study of acute liver failure in children using next generation sequencing technology. Journal of Pediatrics 2021; 236: 124-130.

^{John Pohl, M.D., Book Editor,} ^{is on the Editorial Board of Practical Gastroenterology}

FROM THE PEDIATRIC LITERATURE

Vancomycin to Prevent Clostrioides difficile Infection in Children

Oral vancomycin is used as a treatment for Clostrioides difficile infection (CDI), and adult studies suggest that vancomycin can be used as a preventative therapy to stop recurrence of CDI in patients receiving antibiotics for other reasons. However, no relevant data exists in children, and the authors of this study looked at the effectiveness of this intervention in children at a single academic health system.

This retrospective study occurred over 6 years and included all children with CDI diagnosed by polymerase chain reaction. Patients were identified who had a prior CDI, had a subsequent outpatient or inpatient encounter, and then required intravenous antibiotic usage during the encounter. This group was then divided into patients who did or did not receive oral vancomycin prophylaxis. Patient demographics were obtained on all patients including the identification of NAP1 (North American pulsed-field gel electrophoresis type 1) strains, use of acid suppression medication, and use of probiotics. Oral vancomycin prophylaxis was defined as dosing of 10 mg / kg every 12 hours during antibiotic administration and for 5 days afterwards.

A total of 148 patients were initially identified; however, the final study patient number after utilizing exclusion criteria consisted of 74 patients (30 receiving oral vancomycin prophylaxis; 44 not receiving oral vancomycin prophylaxis). Patients were statistically similar regarding demographics and comorbidities although more males received oral vancomycin prophylaxis (not significant). Most patients had a history of malignancy or immune suppression. There was no difference between groups in regard to acid suppression use or probiotic use. Hospital length of stay was longer in patients who received oral vancomycin prophylaxis. Most patients had only one prior CDI, and most patients had received antibiotics within 3 months of CDI. Oral vancomycin prophylaxis was more common in patients who had received fluoroquinolones and carbapenems. Oral vancomycin prophylaxis also was significantly more common in patients receiving 2 or more classes of antibiotics and receiving a longer duration of antibiotics. Patients who did not receive oral vancomycin prophylaxis were statistically more likely to have CDI recurrence. No vancomycinresistant enterococci infection occurred in any patient within 8 weeks of vancomycin exposure. Univariate and multivariate analysis demonstrated that receiving oral vancomycin prophylaxis was the only significant factor associated with a reduced risk of CDI.

Oral vancomycin prophylaxis shows the potential of reducing CDI in at-risk pediatric patients with prior CDI. This is a retrospective study, and prospective data is needed to determine optimal timing and duration of oral vancomycin use. Additionally, the risk of vancomycin resistant enterococci infection still remains a concern in such patients.

^{Bao H, Lighter J, Dubrovskaya Y, Merchan C, Siegfried J, Papadopoulos J, ShinPung J. Oral vancomycin as secondary prophylaxis for Clostrioides difficile infection. Pediatrics 2021; 148: e2020031807.}

FROM THE LITERATURE

High SVR in Treatment of HCV with Suboptimal Dosing Adherence

The impact of efficacy for treatment with directacting antiviral drugs in the treatment of HCV infection with suboptimal adherence, particularly with shorter treatment durations was evaluated further. Evaluation with post-hoc analyses evaluated adherence (based on pill count), in patients prescribed 8- or 12- week Glecaprevir/ Pibrentasvir (G/P), the impact of nonadherence on the SVR at post-treatment week 12 (SVR12), and the factors associated with nonadherence and efficacy in patients interrupting G/P treatment.

Data was pooled from 10 phase 3 clinical trials of treatment-naïve patients with HCV genotype 1-6, without cirrhosis, with compensated cirrhosis (treatment adherence analysis), and 13 phase 3 clinical trials of all patients with HCV (interruption analysis).

A total of 2,149 patients were included. Overall meet adherence was 99.4%. Over the treatment duration, adherence decreased (week 0-4 – 100%; weeks 5-8 – 98.3%, and weeks 9-12; 97.1%). The percentage of patients with greater than 80% or 90% adherence declined. SVR12 rate in the intention-to-treat (ITT) population was 97.7% and remained high in nonadherent patients in a modified ITT population.

Psychiatric disorders were associated with less than 80% adherence and shorter treatment duration was associated with greater than 80% adherence. Among 2,902 patients in the interruption analysis, 33 (1.1%) had a G/P treatment interruption of greater than 1 day with an SVR12 rate of 93.9% (31/33). No virologic failures occurred. The findings support the impact of treatment duration and adherence rate and further reinforce the concept of “treatment forgiveness” with directacting antivirals.

Zamor, P., Brown, A., Dylla, D., et al. “HighSustained Virologic Response Rates of Glecaprevir/Pibrentasvir in Patients with Dosing Interruption or Suboptimal Adherence.” American Journal of Gastroenterology; Vol. 116, September 2021, pp. 1897-1904.

^{Murray H. Cohen, DO, “From the Literature” Editor, is on the Editorial Board of Practical Gastroenterology.}

FROM THE LITERATURE

USDA Efficacy in PBC with Compensated Cirrhosis

A retrospective cohort study of veterans, predominantly men with PBC and compensated cirrhosis were evaluated to assess the association of response to UDCA with the development of all-cause and liver-related mortality for transplantation, hepatic decompensation, and HCC-using, competing risk time-updating Cox proportional hazards models. A total of 501 subjects with PBC and compensated cirrhosis, including 287 UDCA responders, (1692.8 patient-years {PY} of follow-up) and 214 partial responders (838.9 PY of follow-up). The unadjusted rates of hepatic decompensation (3.8 vs 7.9 per 100 PY), and liverrelated death or transplantation (3.7 vs 6.2 per PY), were lower in UDCA responders compared with partial responders. UDCA response was associated with a lower risk of hepatic decompensation (subhazard ratio {sHR} 0.54), death from any cause or transplantation (aHR 0.49), and liverrelated death or transplantation (sHR 0.40), but not HCC (sHR 0.39). In a sensitivity analysis, the presence of portal hypertension was associated with the highest UDCA-associated effect.

It was concluded that UDCA response is associated with a reduction in decompensation, all-cause, and liver-related death or transplantation in a cohort of predominantly male patients with cirrhosis, with the highest benefit in patients with portal hypertension.

^{John, B., Khakoo, N., Schwartz, K., et al. “Ursodeoxycholic Acid Response is Associated with Reduced Mortality in Primary Biliary Cholangitis with Compensated Cirrhosis.” American Journal of Gastroenterology; Vol. 116, September 2021, pp. 1913-1923.}

FROM THE LITERATURE

Ranitidine and Bladder Cancer

With knowledge that the carcinogen N-nitrosodimethylamine and increased urinary content of that component in humans, utilizing that drug to investigate whether ranitidine use is associated with increased bladder cancer risk, a nested, case-control study was conducted within the Primary Care Clinical Informatics Unit Research database, containing general practice records from Scotland. Bladder cancer cases, diagnosed between 1999 and 2011 were identified and matched with up to 5 controls, based on age, sex, general practice and date of registration.

Ranitidine, other H2 receptor agonists and proton pump inhibitors were identified from prescribing records. Odds ratios (ORs) and 95% confidence intervals were calculated using conditional logistic regression after adjusting for comorbidities and smoking.

A total of 3260 cases were reviewed with 14,037 controls. There was evidence of increased risk of bladder cancer in ranitidine users, compared with nonusers (OR = 1.22), which was more marked with use over 3 years of ranitidine therapy (OR = 1.43). By contrast, there was little evidence of any association between PPI use and bladder cancer risk, based on any use (OR = 0.98), or over 3 years of use (OR = 0.98).

In this large population-based study, the use of ranitidine, particularly long-term, was associated with an increased risk of bladder cancer.

^{Cardwell, C., McDowell, R., Hughes, C., et al. “Exposure to Ranitidine and Risk of Bladder Cancer: A Nested, Case-Control Study.” American Journal of Gastroenterology; Vol. 116, August 2021, pp. 1612}–^1619.

FROM THE LITERATURE

Steatosis and Steatohepatitis Effects on Patients with Chronic Hepatitis B

To investigate the impact of fatty liver disease (FLD) on liver disease severity in a large North American cohort with chronic hepatitis B viral infection, liver biopsies from 420 hepatitis B surface antigen-positive adults that were enrolled in the Hepatitis B Research Network and who were not on HBV therapy in the previous month were evaluated for inflammation and fibrosis. Steatohepatitis was based on steatosis, hepatocyte ballooning, with or without Mallory-Denk bodies and perisinusoidal fibrosis. The models evaluated factors associated with steatohepatitis, and the association of steatohepatitis with fibrosis and longitudinal ALT, AST, and Fibrosis-4.

The median age was 42 years and 62.5% were male, 79.5% were Asian. A total of 132 (31.4%) patients had FLD (77 – 18.3%), steatosis only, 55 – 13.1% had steatohepatitis. Older age, overweight/obesity and diabetes were associated with steatohepatitis. Steatohepatitis versus no FLD was associated with 1.6% times higher risk of advanced fibrosis at baseline and there was indication of higher incident cirrhosis rate during followup. Steatohepatitis versus no FLD was also independently associated with 1.39 times higher ALT, 1.25 times higher Fibrosis-4. It was concluded that coexisting steatosis occurred in nearly one-third of adults of which 13% had steatohepatitis with chronic hepatitis B viral infection in this North American cohort who underwent liver biopsies. Steatohepatitis was associated with advanced fibrosis and higher biochemical measures of hepatic inflammation over time. There is indication for screening for and managing metabolic abnormalities in patients with HBV to prevent disease progression in HBV.

^{Khalili, M., Kleiner, D., King, W., et al. for the Hepatitis B Research Network (HBRN). “Hepatic Steatosis and Steatohepatitis in a Large North American Cohort of Adults with Chronic Hepatitis B.” American Journal of Gastroenterology; Vol. 116, August 2021, pp. 1686-1697.}