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1978 —

35th Anniversary — 2013

gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

Volume 64, Number 8 • August 2013

DDW 2013

Risk for Barrett’s Recurrence Rated

Higher Reimbursement an Added Bonus Of Quality Benchmarking Program BY MONICA J. SMITH

BY TED BOSWORTH ORLANDO, FLA.—Researchers have identified predictors for recurrence of Barrett’s esophagus (BE) following radiofrequency ablation (RFA) that may inform guidance on post-RFA surveillance and patient counseling, they reported at the 2013 Digestive Disease Week (DDW) meeting.

BY CAROLINE HELWICK ORLANDO, FLA.—The combination of octreotide and celecoxib, administered within 48 hours of the onset of severe acute pancreatitis (SAP), can prevent worsening of the condition, according to a study reported by investigators from China at the 2013 Digestive Disease Week meeting.

BOSTON—A benchmarkin ng program that sets standards of quality for endoscopy has alllowed participating health care professionals to negotiate better rates of reimbursement with insurance proviiders, researchers told attendees of the third annuaal GI Roundtable, held in Boston in March. “[The program] was not originally viewed as a tool that would be used in contracting, but that is a secondary gain from the fact that if you improve the quality of your care, show by an objective measure that your performance is as good as or better than a benchmark and find a payyor who’s willing to recognize that value, it certainly can work,” said Thomas Deas Jr., MD, medical director, Fort Worth Endoscopy Center, Fort Worth, Texas, and president of the American Society for Gastrointestinal Endoscopy (ASGE).

see Pancreatitis, page 30

see Quality, page 20

see Barrett’s Recurrence, page 10

Drug Combo May Halt Pancreatitis

EXPERT ROUNDTABLE

I N S I D E

Experts Discuss Critical Role of Microbiome in Digestive, Overall Health Microb

HEPATOLOGY

I N

FOCUS

EXPERTS’ PICKS EXPER Top Liver Abstracts From The International Liver Congress/EASL and Digestive Disease Week ......page 22

BY DAVID VID WILD Exxpe perts recently convened in Madrid, Spain at the Gut Microbiota for Health’s 2nd W ld Summit to discuss the latest advances in research in the human microbiome. Worl Gaastrroenterology & Endoscopy News (GEN) interviewed five leading North American gastrroeenterologists who spoke at the conference. Following is what they shared about the growing eevidence of the critical role of the microbiome in digestive and overall health.

Patrick Basu, MD

Jordan Feld, MD, MPH

Jacqueline O’Leary, MD, MPH

see Expert Roundtable, page 14 PRINTER-FRIENDLY VERSION AVAILABLE AT GASTROENDONEWS.COM

PRODUCT ANNOUNCEMENT

CLINICAL REVIEW

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Diagnostic Tests for Helicobacter pylori By Sowjanya Kanna, MD, Carla Maradey-Romero, MD, and Ronnie Fass, MD

Diagnostic tests for Helicobacter pylori

SOWJANYA KANNA MD CARLA MARADEY-ROMERO MD RONNIE FASS MD Department of Medicine Division of Gastroenterology and Hepatology, Esophageal and Swallowing Center MetroHealth Medical Center Case Western Reserve University Cleveland, Ohio

A

human pathogen found primarily in the stomach, Helicobacter pylori is known to play a pivotal role in the development of several gastroenterological conditions like gastritis, gastric mucosa

associated lymphoid tissue (MALT) and peptic ulcer disease.

Currently, there are different tests that are available to detect active infection of H. Pylorii but there is no defined role for routine screening for the bacteria. The tests are divided into those that are invasive and hose that are not non invasive. The invasive tests include histology, rapid urease test, culture and endoscopic urea breath test. The non-invasive tests include serology, urea breath test and stool antigen test. There are several molecular methods for diagnosing H. Pylorii including polymerase chain reaction (PCR), real time PCR and multiplex PCR. Determining which test to use to identify H. Pylorii infection depends on the clinical scenario.

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

Introduction Helicobacter Pylori (H. Pylori) is a human pathogen found primarily in the stomach. The organism is known to have a significant role in the pathogenesis of gastritis, peptic ulcer disease (PUD) and mucosa associated lymphoid tissue (MALT) lymphoma(1). Chronic infection with H. pylorii is endemic, affecting about half of the world population especially those in developing countries. The prevalence is reported to be closely linked to socioeconomic status. However, economic development and the widespread use of antibiotics are likely responsible for the decline in H. pylorii prevalence (2).

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS • AU G U ST 2 0 1 3

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The #1 best-read gastroenterology publication in the USA. Anytime. Anywhere. 1978 —

at

35th Anniversary — 2013

gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

H E PAT O L O G Y IN F O C U S

Guidance Equivocal On HCV Screening Of Baby Boomers

Despite Above Average Income, Gastros Report Job Dissatisfaction BY VICTORIA STERN

BOSTON—Recent evidence suggests that nonalcoholic fatty liver disease (NAFLD) is emerging as a significant public health problem. One study revealed an “alarming” rate of HCC related to NAFLD, even among

Gastroenterologists are the fourth most highly compensated physicians compared with doctors in 24 other medical specialties, according to an online survey conducted by Medscape in February 2013. Average annual income for gastroenterologists was up 13% in 2012 compared with 2011, coming in at $342,000. The three specialties that beat out gastroenterology in average yearly compensation were orthopedists at $405,000, cardiologists at $357,000 and radiologists at $349,000 (see Figure 1, page 28). But despite robust earnings, less than half (48%) of the gastroenterologists surveyed said they felt fairly compensated, the same percentage as that of physicians of all specialties who said they felt fairly compensated. The findings were based on responses collected in a third-party online survey of 21,878 U.S. physicians, 2% of whom were gastroenterologists. Most gastroenterologists who responded were men (84%) and board certified (96%), and 62% were aged 45 years or older.

see NAFLD, page 14

see Income, page 28

BY CHRISTINA FRANGOU Hepatologists have added their voices to the debate over screening for hepatitis C virus (HCV) infection and are urging the U.S. Preventive Services Task Force (USPSTF) to upgrade its current recommendation see HCV Screening, page 18

NAFLD Threatening Public Health BY KATE O’ROURKE

I N S I D E

Cost Sharing for Polyp Removal During Colonoscopy Waived for Some Patients

H E PAT O L O G Y

I N

FOCUS

Investigational Device Prolongs Survival of Livers For Transplantation .................................................page 8

BY MONICA J. SMITH

tor

Ma Vis it y DD 19- us W 21, bo 2 oth 013 15 31

Effect of Preexisting Cardiovascular Disease On Outcomes After Liver Transplantation May Be Underestimated..........................................page 9

Patients with private insurance will no longer be responsible for any cost sharing in the event that a polyp is removed during a screening colonoscopy, according to a recent clarification, issued by the federal government, on preventive screening benefits under the Affordable Care Act (ACA). “This is very good news,” said Durado Brooks, MD, MPH, direcof Prostate and Colorectal Cancers at the American Cancer Society in

Retreatment of Hepatitis C With Interferon Alone May Increase Mortality ..........................................«>}iÊ£È Statins Linked to Reduction in Mortality From Liver Cancer.................................................«>}iÊÓ{

see Cost Sharing, page 32 PRINTER FRIENDLY VERSION AT GASTROENDONEWS.COM

CLINICAL REVIEW see insert between pages 20 and 21

Ulcerative Colitis: Treatment Strategies By Ellen J. Scherl, MD, Arun Swaminath, MD, Brian Bosworth, MD, and Vinita Jacob, MD

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Ulcerative Colitis: Optimizing Mesalamine Sttrategies ELLEN J. SCHERL, MD Director, Jill Roberts Center for Inflammatory Bowel Diseasea Jill Roberts Center for Inflammatory Bowel Disease Director of Researchb Jill Roberts Associate Professor of Inflammatory Bowel Diseaseb Associate Professor of Clinical Medicineb Adjunct Associate Professor of Medicinec

ARUN SWAMINATH, MD Assistant Attending Physiciana Assistant Professor of Clinical Medicinec

BRIAN BOSWORTH, MD

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treat patients with inflamma atory bowel disease (IBD) is to move from symptomoriented (step--up) strategies toward preventio on-orie ented (early intervention) strategies aimed at tight inflammation control and alteration of the natural history of IBD. This review focuses on a personalized approach to the treatment of IBD using 5-aminosalicylic acid (5-ASA) agents.

Assistant Attending Physiciana Assistant Professor of Medicineb Anne and Ken Estabrook Clinical Scholar in Gastroenterologyb

VINITA JACOB, MD Assistant Attending Physiciana Assistant Professor of Medicineb

DANA J. LUKIN, MD, PHD Gastroenterology Fellowc a

b

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NewYork-Presbyterian Hospital/ Weill Cornell Medical Center New York, New York Weill Cornell Medical College New York, New York Columbia University College of Physicians and Surgeons New York, New York

Challenging the Traditional IBD Diagnosis Traditionally, IBD has been divided into 2 distinct entities: ulcerative colitis (UC) and Crohn’s disease (CD). A nuanced view presents IBD as an immunoinflammatory spectrum of chronic and recurring diseases of the intestines defined by individual molecular signatures. This newly gained perspective holds the promise of moving treatment in a more proactive, personalized direction, toward targeting molecules and risk assessment, rather than treating symptoms of the disease. One of the major questions facing clinicians is whether IBD is a single entity or a spectrum of multiple disorders. This distinction becomes particularly difficult to make when attempting to

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS •

2013

1

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1978

35th Anniversary — 2013

The Independ Independent dent Monthly Monthl Newspaper for Gastroenterologists

For more than three decades, Gastroenterology & Endoscopy News has been providing gastroenterology health care professionals with specialty-specific news and reviews, offering comprehensive and objective information for the practicing clinician. 1978 —

35th Anniversary — 2013

gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

Volume 64, Number 1 • January 2013

ACG 2012

IBS No Longer Only Functional Disorder

Experienced Physicians Offer Tips To Trainees on Landing a Job It’s Never Too Early To Start the Search

BY DAVID WILD BY CHRISTINA FRANGOU LAS VEGAS—For the first time, investigators have documented structural abnormalities in the small bowel of patients with irritable bowel syndrome (IBS). These findings “will fundamentally change our thinking on the disease,” researchers told attendees of the 2012 see IBS, page 8

Mesalamine Elicits Response in IBS BY MONICA J. SMITH LAS VEGAS—Mesalamine, a 5-aminosalicyte acid that is effective for maintenance of remission in patients with ulcerative colitis, also may be effective in relieving and controlling symptoms in irritable bowel syndrome see Mesalamine, page 9

If they haven’t already, fellows and residents should add one more resolution to their New Year’s list: Start the job search. The earlier that trainees begin the search, the better, experts say. Many recommend that residents and fellows start the process 18 months before they are due to finish training. With recruiting season kicking into high gear over the next few months, Gastroenterology & Endoscopy Newss summarized some practical tips for finding a job in academic medicine or private practice, as outlined by two gastroenterologists with experience in each area. see Job Search, page 25

Experts’ Picks

I N S I D E

Best of the American College e Of Gastroenterology: Part 2

MDs and DOs Plan Unified Accreditation System For Graduate Medical Education ............... page 5

EXPERT REVIEW: Sexual Misconduct by Professionals: A New Model of Understanding

COMPILED AND WRITTEN BY DAVID WILD Gastroenterology & Endoscopy Newss asked several experts to select their favvorite abstracts from the 2012 American College of Gastroenterology (ACG) Annual Scien ntific Meeting. Inside is a collection of their selections and comments that reflect the varied interests of the experts who we interviewed. (Part 1 of this series appeared in the Decemberr 2012 issue of Gastroenterology & Endoscopy News.) see Best of ACG, page 14

BY GREGORY E. SKIPPER, MD, AND STEPHEN SCHENTHAL, MD..................... page 29

EXPERT REVIEW: Safeguarding Yourself Against Allegations Of Sexual Abuse or Patient Impropriety BY HARVEY TETTLEBAUM, JD, AND KEVIN MEYERS, JD .................................................................. page 33

PRODUCT ANNOUNCEMENT Clinical Applications of Probiotics in Gastroenterology: Questions and Answers, An Issue of Gastroenterology Clinics see page 37

The Gastric Cancers: Targeted for Personalized Medicine see pages 10-11

We are proud to be the best-read gastroenterology publication in the marketplace, and we look forward to continuing to be your #1 source for gastroenterology news in decades to come.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2013

Vol. 64, No. 8 MEDICAL ADVISORY BOARD MANOOP S. BHUTANI, MD

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GASTROENTEROLOGY & ENDOSCOPY NEWS, the independent monthly newspaper for gastroenterologists, has been providing physicians with comprehensive and objective information since 1978. The newspaper is circulated to more than 17,500 gastroenterologists, colorectal surgeons, and hepatologists, and GI-specific physician assistants and nurse practitioners (as reported to BPA Worldwide, Publishers Audit, based on circulation data as of January 2013). Gastroenterology & Endoscopy News (ISSN 0883-8348) is published monthly by McMahon Publishing. Periodicals postage paid at New York, NY, and at additional mailing offices. POSTMASTER: Please send address changes to Gastroenterology & Endoscopy News, 545 W. 45th Street, 8th Floor, New York, NY 10036.

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INFECTIOUS DISEASE SPECIAL EDITION

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for consistently making

the best read publication in the U.S. gastroenterology market More than 17,000 readers* every month: ♌ 780 physician assistants ♌ 13,748 gastroenterologists ♌ 210 nurse practitioners ♌ 1,588 colon and rectal surgeons ♌ 1,059 pediatric gastroenterologists ♌ 120 hepatologists

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N No. 1 readership†, including: ♌ high readers ♌ average issue readers ♌ 4/4 (monthly) readers ♌ cover-to-cover readers * BPA Worldwide, July 2011 † Kantar Media, December 2011


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GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2013

Unsafe Injection Practices Remain All Too Common ISMP Highlights Practices That Put Patients At Risk for Hepatitis, Other Infections HCV-infected patient. Backflow from the injection or from the removal of the needle contaminated the syringe, which was then reused to draw medication from the single-use vial, contaminating the vial and initiating a chain of infection transmission. “What happened there was not unique to Vegas. We see this over and over,” Dr. Perz said during the webinar.

BY DAVID WILD Evelyn McKnight, AuD, has first-hand knowledge of the devastating consequences of unsafe injection practices. In 2001, she contracted hepatitis C while undergoing chemotherapy for breast cancer. An investigation into the source of Dr. McKnight’s infection by the state health department and Centers for Disease Control and Prevention (CDC) uncovered “dumbfounding and unsettling” findings, she said. For 16 months, a clinic nurse had been reusing syringes to draw saline solution from a common IV bag during port-flushing procedures in advance of administering chemotherapy. In the process, hepatitis C virus (HCV) infection from a previously infected patient was spread to 99 others. “The irony is that I traded one lifethreatening disease for another,” said Dr. McKnight, founder of HONOReform Foundation, a national advocacy organization dedicated to safeguarding injection practices. She spoke during an Institute for Safe Medication Practices (ISMP) webinar held on May 9. Matthew Fricker, RPh, MS, program director at ISMP, said he worries that outbreaks like the one Dr. McKnight experienced are only the tip of the iceberg and that many others remain unreported. Results from the 2011 ISMP Medication Safety Self Assessment for Hospitals support this concern, he said. Of the more than 1,300 hospitals that completed the assessment, 2% had not implemented any policy prohibiting the use of multiple-dose vials for saline and heparin flush solutions or for local anesthetics, and 24% had only partially implemented such a policy. Two percent had only partially implemented a hospital-wide policy prohibiting the reuse of the same syringe in more than one patient even if the needle had been changed between patients. According to Mr. Fricker, 2% may seem like an insignificant number, but when it comes to injection practices, small mistakes can have significant consequences. “We need to be at 100% adherence for these practices,” he emphasized. Recent reports of insulin pens being reused—including one reported shortly after the webinar (Whitman V. “Catskill hospital warns that insulin pens may have been reused” Times Herald-Record, d May

Education Needed

A look at the outbreak of HCV that occurred in Las Vegas in 2008 illustrates how the reuse of syringes and single-dose vials can lead to rapid exposure to infectious diseases in large numbers of individuals.

21, 2013)—have placed nearly 5,000 patients at risk for infection with HIV, HCV or hepatitis B virus. Mr. Fricker noted. In the ISMP hospital assessment, 9% of hospitals said they had not taken any formal steps to implement a policy prohibiting the use of multidose pens as unit stock. The misuse of insulin pens has prompted the ISMP to recommend that hospitals consider transitioning away from using pen devices. “Issuing this recommendation was not a decision we made lightly,” Mr. Fricker said. A look at the outbreak of HCV that occurred in Las Vegas in 2008 illustrates how reuse of syringes and single-dose vials can lead to rapid exposure to infectious diseases in large numbers of individuals,

said Joseph Perz, DrPH, team leader in ambulatory and long-term care in the Prevention and Response Branch at the CDC’s Division of Healthcare Quality Promotion. That outbreak started with a clean needle and syringe that had initially been used to draw from a single-use vial and administer the medication to an

Dr. Perz said he believes that many of these lapses in safe practice are due to a lack of understanding as to what constitutes safe injection practices. “To even get nurses to recognize the difference between a single- and multipledose vial requires significant effort,” Dr. Perz told ISMP webinar attendees. “We need to train our providers just to read the label. Unless it is a manufactured vial with the term ‘multidose vial’ printed on it, it is not a multidose vial.” Results from a 2010 survey of 5,000 health care workers, most of whom were nurses, illustrates the disparity between how well clinicians believe they are doing in preventing infections and how they behave, Mr. Fricker said (Pugliese G et al. Am J Infect Control 2010;38:789-798). Although most respondents said they followed recommended infection control practices, 6% said they sometimes or always used single-dose vials for multiple patients and 1% said they reused a syringe for more than one patient after discarding the needle. “There is a misconception that changing a needle is enough to be safe,” Mr. Fricker said. “Many of these respondents were unaware of the risk for spreading disease after changing a needle but reusing the same vial.” Dr. Perz urged webinar attendees to share the CDC’s Injection Safety Checklist (www.cdc.gov/ injectionsafety) and to visit ONEandONLYcampaign.org for free staff training activities, brief how-to videos and posters emphasizing the importance of using single-dose vials and insulin pens in only one individual. Dr. Perz concluded, “I don’t think we can do enough to educate providers on what safe practices are.” ■


7

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2013

Private Practice Is a Dinosaur and the ACA Is an Asteroid Nicholas V. Costrini MD, PhD, MBA Gastroenterologist in solo practice Georgia Gastroenterology Group, PC Savannah, Georgia

After reigning over the earth for more than 250 million years, it all came to an end 65 million years ago. The dinosaur was done, and many offer that an asteroid struck the Yucatan Peninsula causing immediate and longterm environmental changes that left only the lonely bird as an evolutionary footnote and paleontologic reminder of the dinosaur’s existence. Although the Yucatan disaster indeed may have been the final catastrophic extinction event, other ecologic forces were at play and also may have contributed to the demise of the dinosaur. Coconspirators in the probable 1 million-year pre-Yucatan dinosaur decline include the increasing mammal population; continental drift; decreasing sea levels; and volcanic eruption, resulting in blockage of sunlight. Researchers are not exactly sure what ended the dinosaur reign—it was probably a combination of events. Interesting, but what does this have to do with the future of private practice gastroenterology? Over the next several decades, the private practice of medicine, and more specifically, the high-volume, highreimbursement subspecialty private practices, such as gastroenterology, will be like the lonely bird. They will be present, but mostly will be a reminder of a medical and sociologic past and no longer will dominate medical care. Numerous factors will contribute to the future of how medical care will be delivered. As in the natural world, these factors should not be judged as good or bad, but rather as evolutionary events that, in their totality, will change the nature of things, namely medical care. If mammals replaced the dinosaur as the higher life form, we can hope that the evolution of medical care will offer a better form of health care than currently exists.

The Decline of Private Practice Although many consider the Patient Protection and Affordable Care Act (ACA) as the primary threat to the existence of private gastroenterology practice, I offer that it is an important, but not the only, cause of the decline of the private health care sector. In fact, the ACA became possible only as a result of the antecedent conspirators against private medical practice. The first of these factors is the disposition of the modern workforce. Private practice is a self-driven, work ethic– dependent, professional-life priority venture. It represents the ethics, values and priorities of traditional American life. The sociologic and personal credo of making success, work and achievement the highest priority, with family, personal life, rest, balance and quality of life following that lead, has been challenged by the millennial generation. Any human resource executive, practice manager or division chief will tell you this. Millennials are smart, fast, eager, group-oriented and most importantly, place the highest priority on quality of life and balance of personal and work arenas. The new generation of physicians has no desire to accept the challenges, workload, fatigue and emotional stress of private medical practice. The demands of private practice, independent of financial considerations, do not match their view of the role of work in their lives. Over the past decade, the percentage of graduating, subspecialty physicians seeking or accepting positions in solo or small private practices has dwindled to single digits, and

Over the next several decades, the private practice of medicine, and more specifically, the high-volume, high-reimbursement subspecialty private practices, such as gastroenterology, will be present, but mostly will be a reminder of a medical and sociologic past and no longer will dominate medical care. the ACA has not yet been minimally implemented. The millennial generation is a major factor that is reducing the viability of the private practice future. Second, there are shifting demographics. The United States has come to the economic brink of disaster with the rising costs of caring for its citizens. In the coming decades, the population of the then-elderly will grow to such a point that the costs of care will be unsustainable. It is worth stating that the additional covered lives with the ACA will represent only 15% of the added population needing care in the next four or more decades. Third, efforts to contain costs by statewide universal health care systems, health management organizations, vertically integrated medical systems and so on, have been present for decades and have served as a prelude to the ACA. Finally, the ACA is here because the country has accepted the gradually evolving political and sociologic concept of the rest of the modern world—that it must have universal health care, and it must find a way to pay for it. This realization—like the rise of the mammal, the shift of the continents and the effect of volcanic gases—paved the way for the exclamation point of the Yucatan asteroid of private practice, namely the ACA.

The Rise of the ACA The ACA seeks to eliminate private practice because that form of medical delivery—namely fee-for-service, individual doctor–patient relationships and owner– entrepreneurial status—cannot be aligned with its goals, which are to organize care around patient populations with large health care systems; to control costs by various maneuvers, such as accountable care organizations, bundling and shared financial risk by clinicians; and to reduce subspecialty care in general. The mechanics of the ACA also promote the extinction of private practice in two obvious ways: 1. the burden of cost and regulatory compliance with electronic health management systems, which are

demanded in the still-elusive names of quality and value, and 2. the reduction in reimbursements for high-cost and high-volume procedures. The business of medicine—the individual entrepreneurial focus of private practice—will succumb to the reality that the cost of running a private business will not be supported by the reimbursements allowed by the ACA. Over the past decade, gastroenterologists have worked harder and longer hours, and have performed perhaps 30% more relative value units annually in order to keep their salaries high and pay the bills. There is no longer a place to go, a way to run faster. And the new generation of doctors would not choose these routes anyway, nor should they. In this respect, the ACA will succeed because the new generation of doctors has evolved in a way that makes the legislation tailor-made for their priorities. This is not a criticism. As in the natural world, change happens. The current flow of private physicians into larger groups is consistent with the priorities of younger physicians, the economic realities of older physicians, the intent of the ACA and the means to cope with the regulatory requirements of a government-directed health care system. The idea that doctors are joining hospitals simply for large signing bonuses dismisses the larger social, political and economic realities of the evolving medical landscape. I would encourage gastroenterologists to join the new order: Do not push harder or run faster, but rather find ways to integrate; reduce office and personnel costs; continue to view your profession in evolutionary terms; and above all, take time to appreciate your contributions to your fellow man. The public does. In the process, however, if you choose to be a bird and remain solo or in a small group practice, you can tell the next generation what it was like to rule the earth. They will be in awe, but will not understand. ■ Dr. Costrini can be reached via email at drcostn@gmail.com.


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DDW 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2013

Barrett’s Recurrence continued from page 1

Longer lesion segment and worse pretreatment histology predicted an increased risk for recurrence of BE after RFA, and both factors are relevant when considering how often to re-evaluate BE patients after treatment, said study author William J. Bulsiewicz, MD, a fellow in the Division of Gastroenterology,

University of North Carolina at Chapel Hill School of Medicine. Dr. Bulsiewicz and his colleagues examined data from the U.S. RFA Registry, a prospective registry of more than 5,000 patients with BE treated with RFA at 148 institutions nationwide, including 113 community-based practices. In one study, Dr. Bulsiewicz and his colleagues sought to identify risk factors for BE recurrence after successful

RFA treatment. In another study, the goal was to specify the rates and timing of recurrence of intestinal metaplasia after complete eradication with RFA treatment. Dr. Bulsiewicz’s team identified 1,128 patients who met the criteria for analysis, which included complete eradication of intestinal metaplasia by RFA, at least two years of follow-up after complete eradication and at least two biopsies

obtained during follow-up. Recurrence was defined as any biopsy from the tubular esophagus showing evidence of intestinal metaplasia. Recurrence was documented in 28% of patients after a mean of 2.2 years (up to 3.3 years) of follow-up. In an additional 9% of patients, empiric RFA retreatment was performed on the basis of a suspected recurrence without histologic confirmation. Among those for

Longer lesion segment and worse pretreatment histology predicted an increased risk for recurrence of BE after RFA, and both factors are relevant when considering how often to re-evaluate BE patients after treatment.

In Active, Mild to Moderate Ulcerative Colitis (UC)1

INDICATIONS AND USAGE UCERIS™ is a glucocorticosteroid indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis. DOSAGE AND ADMINISTRATION The recommended dosage of UCERIS is one 9-mg tablet to be taken once daily in the morning with or without food for up to 8 weeks.

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS UCERIS is contraindicated in patients with known hypersensitivity to budesonide or any of the ingredients of UCERIS. WARNINGS AND PRECAUTIONS t)ZQFSDPSUJDJTNBOEBESFOBMTVQQSFTTJPO4JODF6$&3*4JTB glucocorticosteroid, general warnings concerning glucocorticoids should be followed. t5SBOTGFSSJOHQBUJFOUTGSPNTZTUFNJDDPSUJDPTUFSPJET Risk of impaired adrenal function when transferring from oral steroids with high systemic effects. Taper patients slowly from systemic corticosteroids if transferring to UCERIS. t*NNVOPTVQQSFTTJPO1PUFOUJBMXPSTFOJOHPGJOGFDUJPOT FH  existing tuberculosis, fungal, bacterial, viral, or parasitic

infection; or ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. t*ODSFBTFETZTUFNJDHMVDPDPSUJDPJETVTDFQUJCJMJUZ3FEVDFEMJWFS function affects the elimination of glucocorticosteroids. t0UIFSHMVDPDPSUJDPJEFGGFDUT$BVUJPOTIPVMECFUBLFOJOQBUJFOUT with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where glucocorticosteroids may have unwanted effects. ADVERSE REACTIONS Most common adverse reactions (incidence ≼2%) are headache, nausea, decreased blood cortisol, upper abdominal pain, fatigue, flatulence, abdominal distension, acne, urinary tract infection, arthralgia, and constipation. DRUG INTERACTIONS Avoid Cytochrome P450 3A4 inhibitors (eg, ketoconazole, grapefruit juice). May cause increased systemic corticosteroid effects. USE IN SPECIFIC POPULATIONS )FQBUJDJNQBJSNFOU.POJUPSQBUJFOUTGPSTJHOTBOEPSTZNQUPNT of hypercorticism.

The Important Safety Information does not include all of the information needed to use UCERIS safely and effectively. Please see Brief Summary of Prescribing Information on the following page and Full Prescribing Information at www.UCERIS.com.


DDW 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2013

11

A multivariate analysis revealed that length of BE lesion whom histology was available, recurrence was either nondysplastic or indefinite for dysplasia in 87% of patients. In the first study, researchers found that 317 of the 1,128 patients who met the study criteria had recurrence of BE, and 811 patients did not. They found that patients with recurrence had longer lesion segments (average, 4.4 vs. 3.9 cm; P=0.01), more advanced age (mean, 63.3 vs. 60.5 years; P=0.0002), a

segment and age, along with non-white race, were independent predictors of BE recurrence after RFA.

higher rate of pretreatment fundoplication (8% vs. 5%; P=0.03) and more evidence of dysplasia prior to RFA (57% vs. 50%; P=0.047). A multivariate analysis

revealed that length of lesion segment (which increased the odds ratio [OR] for recurrence by 9% for each additional centimeter) and age (which increased

UCERIS™:

A POWERFUL, LOCALLY ACTING STEROID1-3 t

MMX® technology targets delivery of budesonide throughout the full length of the colon1,2

t

3 times more patients taking UCERIS achieved combined clinical remission and mucosal healing compared with placebo3*

A SAFETY PROFILE THAT OFFERS CONFIDENCE1 t The rates of overall expected glucocorticoid-related side effects were similar for UCERIS

and placebo at 8 weeks—10.2% vs 10.5%, respectively1*

www.UCERIS.com CORE STUDY DESIGNS: Two randomized, double-blind, placebo-controlled studies were conducted in a total of 899 adult patients with active, mild to moderate UC (Ulcerative Colitis Disease Activity Index [UCDAI]: ≥4 and ≤10 at entry). The primary endpoint was induction of combined clinical remission and mucosal healing (defined as a UCDAI score of ≤1, with scores of 0 for both rectal bleeding and stool frequency, normal mucosa with no friability on endoscopy, and a ≥1-point reduction in the endoscopic index [EI] score) after 8 weeks of treatment.1 *In a pooled analysis of 2 Phase III clinical trials.1,3 References: 1. UCERIS Prescribing Information. Santarus, Inc. January 2013. 2. Brunner M, Ziegler S, Di Stefano AF, et al. Gastrointestinal transit, release and plasma pharmacokinetics of a new oral budesonide formulation. Br J Clin Pharmacol. 2005;61:31-38. 3. Data on file. Santarus, Inc. UCERIS is a trademark of Santarus, Inc. MMX is a registered trademark of Cosmo Technologies, Ltd.

© 2013 Santarus, Inc. 1-UCE13229 June 2013 Printed in the USA.

risk for recurrence by 2% for each year of age), along with non-white race (OR, 1.69), were independent predictors of recurrence. Additionally, an increasing number of RFA sessions before eradication was associated with a reduced risk for recurrence (OR, 0.85 per session). “Likelihood for recurrence was not influenced by sex, pretreatment dysplasia, treatment with endoscopic mucosal see Barrett’s Recurrence, page 12


12

DDW 2013

Barrett’s Recurrence continued from page 11

resection, or treatment at an academic versus a community-based practice in multivariate analysis,� Dr. Bulsiewicz noted. In the second study, the same data were used to examine the timing of recurrence. Patients were stratified by pre-RFA histology, and recurrences were then evaluated within these groups. Of the 1,128 patients, pre-RFA histology was nondysplastic BE in 461 patients (41%), high-grade dysplasia (HGD) in

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2013

301 patients (27%), low-grade dysplasia (LGD) in 216 patients (19%), indefinite dysplasia in 80 patients (7%), intramucosal carcinoma in 61 patients (5%) and esophageal adenocarcinoma in nine patients (1%). Recurrences occurred 1.3 years after RFA on average. The researchers found that not only were patients with more advanced pre-RFA histology more likely to have a recurrence, but the time to recurrence was shorter, and the histology at the time of recurrence was more advanced. For example, the average recurrence rate per

year was 17% in the HGD group compared with 12% in the nondysplastic disease group (P=0.002). At recurrence, intramucosal carcinoma was observed in 5% of patients with HGD prior to treatment compared with none of those who had nondysplastic BE. The findings from these studies, which were obtained from “the largest reported cohort of patients treated with RFA for BE,� led Dr. Bulsiewicz to suggest that more frequent surveillance after RFA appears to be warranted in patients with advanced histology prior

‘These results highlight that up to one-third of patients can have recurrent BE after apparent successful ablation. On the basis of these findings, continued surveillance is a must and patients should be informed about this, prior

BRIEF SUMMARY Please see package insert for Full Prescribing Information available at www.uceris.com UCERIS (budesonide) extended release tablets, for oral use Rx Only INDICATIONS AND USAGE UCERIS (budesonide) extended release tablets are indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis. CONTRAINDICATIONS UCERIS is contraindicated in patients with hypersensitivity to budesonide or any of the ingredients of UCERIS. Anaphylactic reactions have occurred with other budesonide formulations. WARNINGS AND PRECAUTIONS Hypercorticism and Adrenal Axis Suppression When glucocorticosteroids are used chronically, systemic effects such as hypercorticism and adrenal suppression may occur. Glucocorticosteroids can reduce the response of the hypothalamuspituitary-adrenal (HPA) axis to stress. In situations where patients are subject to surgery or other stress situations, supplementation with a systemic glucocorticosteroid is recommended. Since UCERIS is a glucocorticosteroid, general warnings concerning glucocorticoids should be followed. Transferring Patients from Systemic Glucocorticosteroid Therapy Care is needed in patients who are transferred from glucocorticosteroid treatment with higher systemic effects to glucocorticosteroids with lower systemic effects, such as UCERIS, since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of glucocorticosteroid treatment with high systemic effects should be reduced cautiously. Immunosuppression Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible patients or patients on immunosuppressant doses of glucocorticosteroids. In patients who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route and duration of glucocorticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior glucocorticosteroid treatment to the risk is also not known. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See prescribing information for VZIG and IG.) If chicken pox develops, treatment with antiviral agents may be considered. Glucocorticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections. Replacement of systemic glucocorticosteroids with UCERIS tablets may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug. Increased Systemic Glucocorticoid Susceptibility Reduced liver function affects the elimination of glucocorticosteroids, and increased systemic availability of oral budesonide has been demonstrated in patients with liver cirrhosis. Other Glucocorticosteroid Effects Caution should be taken in patients with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where glucocorticosteroids may have unwanted effects. ADVERSE REACTIONS Systemic glucocorticosteroid use may result in the following: t )ZQFSDPSUJDJTNBOE"ESFOBM4VQQSFTTJPO t 4ZNQUPNTPGTUFSPJEXJUIESBXBMJOUIPTFQBUJFOUTUSBOTGFSSJOH from Systemic Glucocorticosteroid Therapy t *NNVOPTVQQSFTTJPO t *ODSFBTFE4ZTUFNJD(MVDPDPSUJDPTUFSPJE4VTDFQUJCJMJUZ t 0UIFS(MVDPDPSUJDPTUFSPJE&GGFDUT Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of UCERIS has been evaluated in controlled and open-label clinical trials which enrolled a combined total of 1105 patients with ulcerative colitis. In two 8-week, placebo-controlled studies in patients with active disease (Study 1 and Study 2), a total of 255 patients received UCERIS 9 mg, 254 patients received UCERIS 6 mg, and 258 patients received placebo. They ranged in age from 18-77 years (mean 43), 56% were male, and 75% were Caucasian. The most common adverse reactions were headache, nausea, decreased blood cortisol, upper abdominal pain, fatigue, flatulence, abdominal distension, acne, urinary tract infection, arthralgia, and constipation. The adverse reactions occurring in 2% or more of patients on therapy with UCERIS 9 mg are summarized in Table 1. Table 1. Summary of Adverse Reactions in Two Placebo Controlled Trials Experienced by at Least 2% of the UCERIS 9 mg Group (Studies 1 and 2)

Headache Nausea Decreased Blood Cortisol Upper Abdominal Pain Fatigue Flatulence Abdominal Distension Acne Urinary Tract Infection Arthralgia Constipation

UCERIS 9 mg (N = 255) n (%) 29 (11.4) 13 (5.1)

UCERIS 6 mg (N = 254) n (%) 37 (14.6) 12 (4.7)

Placebo (N = 258) n (%) 27 (10.5) 11 (4.3)

11 (4.3)

6 (2.4)

1 (0.4)

10 (3.9)

8 (3.1)

5 (1.9)

8 (3.1) 6 (2.4) 6 (2.4) 6 (2.4) 5 (2.0) 5 (2.0) 5 (2.0)

5 (2.0) 8 (3.1) 4 (1.6) 2 (0.8) 1 (0.4) 5 (2.0) 1 (0.4)

5 (1.9) 5 (1.9) 2 (0.8) 5 (1.9) 1 (0.4) 4 (1.6) 2 (0.8)

0G6$&3*4NHQBUJFOUT BUPUBMPGEJTDPOUJOVFEUSFBUNFOUEVF to any adverse event (including adverse reactions) compared with 17% in the placebo group. Table 2 summarizes the percentages of patients reporting glucocorticoid related effects in the 2 placebocontrolled studies. Table 2. Summary of Glucocorticoid Related Effects in Two Placebo-Controlled Trials (Studies 1 and 2)

0WFSBMM Mood changes Sleep changes Insomnia Acne Moon face Fluid retention Hirsutism Striae rubrae Flushing

UCERIS 9 mg (N = 255) n (%) 26 (10.2) 9 (3.5) 7 (2.7) 6 (2.4) 6 (2.4) 3 (1.2) 2 (0.8) 1 (0.4) 0 0

UCERIS 6 mg (N = 254) n (%) 19 (7.5) 10 (3.9) 10 (3.9) 6 (2.4) 2 (0.8) 3 (1.2) 3 (1.2) 0 0 1 (0.4)

Placebo (N = 258) n (%) 27 (10.5) 11 (4.3) 12 (4.7) 8 (3.1) 5 (1.9) 4 (1.6) 3 (1.2) 0 2 (0.8) 3 (1.2)

No clinically significant differences were observed with respect to the overall percentages of patients with any glucocorticoid related effects between UCERIS and placebo after 8 weeks of induction therapy. Study 3 was an open-label study evaluating UCERIS 9 mg once daily for 8 weeks in 60 patients who had previously completed an 8-week induction study (Study 1), but had not achieved remission. Among patients who took UCERIS 9 mg up to 16 weeks cumulatively across Study 1 and Study 3 combined, similar rates of adverse reactions and glucocorticoid-related effects were seen compared to those who took UCERIS 9 mg for 8 weeks in Study 1. In Study 4, the safety of long-term treatment with UCERIS 6 mg was evaluated in a placebo-controlled 12-month maintenance study of 123 patients. Patients who had previously completed 8 weeks of therapy in any induction study (Study 1, 2, or 3) and were in remission were randomized to UCERIS 6 mg or placebo once daily for 12 months. In patients who took UCERIS 6 mg for up to 12 months, similar rates of adverse reactions were seen between placebo and UCERIS 6 mg. After up to 12 months of study treatment, 77% (27/35) of the patients in the UCERIS 6 mg and 74% (29/39) of the patients in the placebo treatment groups had normal bone density scans. In Study 4, the glucocorticoid related effects were similar in patients with up to 12 months of therapy with UCERIS 6 mg and placebo. (Table 3) Table 3. Summary of Glucocorticoid Related Effects Over 12-month Treatment (Study 4)

0WFSBMM Insomnia Mood changes Moon face Sleep changes Acne Hirsutism Flushing Fluid retention

UCERIS 6 mg (N = 62) n (%) 9 (14.5) 4 (6.5) 4 (6.5) 3 (4.8) 3 (4.8) 3 (4.8) 3 (4.8) 1 (1.6) 1 (1.6)

Placebo (N = 61) n (%) 7 (11.5) 4 (6.6) 2 (3.3) 3 (4.9) 3 (4.9) 0 0 1 (1.6) 1 (1.6)

Postmarketing Experience The following adverse reactions have been identified during postapproval use of oral budesonide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders: anaphylactic reactions Nervous System Disorders: benign intracranial hypertension Psychiatric Disorders: mood swings DRUG INTERACTIONS Interaction with CYP3A4 inhibitors Concomitant oral administration of ketoconazole (a known inhibitor of CYP3A4 activity in the liver and in the intestinal mucosa) caused an eightfold increase of the systemic exposure to oral budesonide. If treatment with inhibitors of CYP3A4 activity (such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin) is indicated, discontinuation of UCERIS should be considered. After extensive intake of grapefruit juice (which inhibits CYP3A4 activity predominantly in the intestinal mucosa), the systemic exposure for oral budesonide increased about two times. Ingestion of grapefruit or grapefruit juice should be avoided in connection with UCERIS administration. Inhibitors of Gastric Acid Secretion Since the dissolution of the coating of UCERIS is pH dependent, the release properties and uptake of the compound may be altered when UCERIS is used after treatment with gastric acid reducing agents (e.g., PPIs, H2 blockers and antacids). USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Pregnancy Category C Budesonide was teratogenic and embryocidal in rabbits and rats. Budesonide produced fetal loss, decreased pup weights, and skeletal abnormalities at subcutaneous doses of 25 mcg/kg in rabbits (approximately 0.05 times the maximum recommended human dose on a body surface area basis) and 500 mcg/kg in rats (approximately 0.5 times the maximum recommended human dose on a body surface area basis). There are no adequate and wellcontrolled studies in pregnant women. Budesonide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects:: Hypoadrenalism may occur in infants born of mothers receiving glucocorticosteroids during pregnancy. Such infants should be carefully observed. Nursing Mothers The disposition of budesonide when delivered by inhalation from a dry powder inhaler at doses of 200 or 400 mcg twice daily for at least 3 months was studied in eight lactating women with asthma from 1 to 6 months postpartum. Systemic exposure to budesonide in these women appears to be comparable

to that in non-lactating women with asthma from other studies. Breast milk obtained over eight hours post-dose revealed that the maximum budesonide concentration for the 400 and 800 mcg total daily doses was 0.39 and 0.78 nmol/L, respectively, and occurred within 45 minutes after inhalation. The estimated oral daily dose of budesonide from breast milk to the infant is approximately 0.007 and 0.014 mcg/kg/day for the two dose regimens used in this study, which represents approximately 0.3% to 1% of the dose inhaled by the mother. Budesonide plasma concentrations obtained from five infants at about 90 minutes after breast feeding (and about 140 minutes after drug administration to the mother) were below quantifiable levels (<0.02 nmol/L in four infants and <0.04 nmol/L in one infant). The recommended daily dose of UCERIS extended release tablets is higher (9 mg daily) compared with inhaled budesonide (up to 800 Îźg daily) given to mothers in the above study. The maximum budesonide plasma concentration following a 9 mg daily dose (in both single- and repeated-dose pharmacokinetic studies) of oral budesonide is approximately 5-10 nmol/L which is up to 10 times higher than the 1-2 nmol/L for an 800 mcg daily dose of inhaled budesonide at steady state in the above inhalation study. Since there are no data from controlled trials on the use of UCERIS by nursing mothers or their infants, and because of the potential for serious adverse reactions in nursing infants from UCERIS, a decision should be made whether to discontinue nursing or to discontinue UCERIS, taking into account the clinical importance of UCERIS to the mother. Budesonide, is secreted in human milk. Data from budesonide delivered via dry powder inhaler indicates that the total daily oral dose of budesonide available in breast milk to the infant is approximately 0.3% to 1% of the dose inhaled by the mother. Assuming the coefficient of extrapolation between the inhaled and oral doses is constant across all dose levels, at therapeutic doses of UCERIS, budesonide exposure to the nursing child may be up to 10 times higher than that by budesonide inhalation. Pediatric Use Safety and effectiveness of UCERIS in pediatric patients have not been established. Glucocorticosteroids, such as UCERIS may cause a reduction of growth velocity in pediatric patients. Geriatric Use Clinical studies of UCERIS did not include sufficient numbers of subjects aged 65 and over to determine whether they SFTQPOEEJGGFSFOUMZGSPNZPVOHFSTVCKFDUT0UIFSSFQPSUFEDMJOJDBM experience has not identified differences in responses between the elderly and younger patients. In general, UCERIS should be used cautiously in elderly patients due to the potential for decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Hepatic Impairment Patients with moderate to severe liver disease should be monitored for increased signs and/or symptoms of hypercorticism. Discontinuing the use of UCERIS tablets should be considered in these patients. OVERDOSAGE Reports of acute toxicity and/or death following overdosage of glucocorticosteroids are rare. Treatment consists of immediate gastric lavage or emesis followed by supportive and symptomatic therapy. If glucocorticosteroids are used at excessive doses for prolonged periods, systemic glucocorticosteroid effects such as hypercorticism and adrenal suppression may occur. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage may be reduced temporarily. Single oral budesonide doses of 200 and 400 mg/kg were lethal in female and male mice, respectively. The signs of acute toxicity were decreased motor activity, piloerection and generalized edema. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity Carcinogenicity studies with budesonide were conducted in rats and mice. In a two-year study in SpragueDawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.023 times the maximum recommended human dose on a body surface area basis) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In an additional two-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). The concurrent reference glucocorticosteroids (prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.1 times the maximum recommended human dose on a body surface area basis). Mutagenesiss Budesonide was not genotoxic in the Ames test, the mouse lymphoma cell forward gene mutation (TK+/â&#x20AC;&#x201C;) test, the human lymphocyte chromosome aberration test, the Drosophila melanogasterr sex-linked recessive lethality test, the rat hepatocycte UDS test and the mouse micronucleus test. Impairment of Fertilityy In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (approximately 0.07 times the maximum recommended human dose on a body surface area basis). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.02 times the maximum recommended human dose on a body surface area basis) and above. No such effects were noted at 5 mcg/kg (approximately 0.005 times the maximum recommended human dose on a body surface area basis).

UCERISâ&#x201E;˘ is a trademark of Santarus, Inc. U.S. Patent Nos: 7,410,651; 7,431,943; RE43799; 8,293,273. Š 2013 Santarus, Inc.

1-UCE13033 V1

to starting ablation.â&#x20AC;&#x2122; â&#x20AC;&#x201D;Prateek Sharma, MD

to treatment. He also suggested that these outcomes might be useful for counseling patients about the relative efficacy of RFA when this treatment is being considered. Prateek Sharma, MD, professor in the Division of Gastroenterology and Hepatology, University of Kansas School of Medicine, Kansas City, Mo., called the data â&#x20AC;&#x153;important,â&#x20AC;? noting that data from the registry provide a valuable realworld perspective that is not available from single-center studies. Dr. Sharma also pointed out that one of the most significant findings of the study was the rate of recurrence after treatment. â&#x20AC;&#x153;These results highlight that up to one-third of patients can have recurrent BE after apparent successful ablation. On the basis of these findings, continued surveillance is a must, and patients should be informed about this prior to starting ablation,â&#x20AC;? he concluded. â&#x2013;  Dr. Bulsiewicz reported no relevant conflicts of interest. Dr. Sharma has received grant and research support from Cook Medical, NinePoint Medical Inc., Olympus America, Inc. and Takeda Pharmaceutical Company Ltd.


13

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2013

From the Literature

Multimodal Endoluminal Therapy Successful for Eradication Of Intestinal Metaplasia in Barrett’s Esophagus p g But Long-Term Follow-Up Reveals High Rate of Recurrence BY MAUREEN SULLIVAN A recent study has shown that in selected patients with Barrett’s esophagus (BE) and high-grade dysplasia (HGD) and/or intramucosal carcinoma, a combination of endoluminal therapies can completely eliminate neoplasia in 95% of cases and intestinal metaplasia in 83% of cases. However, long-term follow-up revealed intestinal metaplasia in more than one-third of patients in whom intestinal metaplasia was initially eradicated. Published earlier this year in Gastrointestinal Endoscopyy (Guarner-Argente C et al 2013;77:190-199), the objective of the research was to “assess the long-term outcomes of patients treated with endoluminal therapy, with the goal of complete eradication of all dysplasia and intestinal metaplasia.” “One-third of the patients in followup had recurrence of intestinal metaplasia. This high rate of recurrence warrants close surveillance,” said Vani Konda, MD, gastroenterologist and assistant professor of medicine at University of Chicago Medicine, who was not involved in the study. “Recurrence also was noted as far out as 83 months, suggesting that surveillance should be continued indefinitely,” she added.

High Rate of Treatment Success In the retrospective cohort study, researchers from the University of Pennsylvania evaluated the medical records of patients who were referred to the Hospital of the University of Pennsylvania between January 1998 and December 2009. Exclusion criteria included patients with invasive carcinoma by endoscopic resection at first treatment endoscopy; patients without confirmation of HGD and/or intramucosal carcinoma at the time of the initial staging biopsy or after an internal review of referring pathology slides; those unfit for intent-to-complete eradication of all BE because of age or comorbidities; and those who previously had esophageal surgery or endoscopic treatment for BE. Initially, 176 patients with BE and suspected HGD and/or intramucosal cancer were identified. BE was defined as the presence of intestinal metaplasia anywhere in the esophagus and/or in the esophagogastric

junction, and was graded using the Prague C & M Criteria. The existence of HGD or intramucosal carcinoma was confirmed by histopathology from biopsies and/or endoscopic resection. The majority of patients, 145 (82%), were men, and the mean age was 68 years. Eighty-three patients (47%) had long-segment BE (length ≥3 cm), and 93 (53%) had short-segment BE (length <3 cm). The pretreatment indication was HGD in 126 patients, but after an initial treatment session that incorporated endoscopic resection, 21 patients were upstaged to intramucosal cancer. At final assessment, 105 patients (60%) were diagnosed with HGD and 71 (40%) with intramucosal cancer. Of the initial 176 patients, 166 were treated and had at least one year of follow-up, for an average of 33 months (range, 18-58 months). Endoluminal therapy consisted of a combination of endoscopic mucosal resection and photodynamic therapy, argon plasma beam coagulation and/or radiofrequency ablation. Treatment was individualized according to patient profile, the nature of the lesions, evolution of the technique and treatment interval response. According to the investigators, “resection and ablation techniques were combined and individualized based on the length and configuration of intestinal metaplasia, unifocality or multifocality of dysplasia, the presence or absence of nodular BE, technique evolution and response to therapies. Treatment was applied every six to 24 weeks until complete eradication of dysplasia, neoplasia and intestinal metaplasia” was achieved. “A singletreatment endoscopy achieved complete eradication of dysplasia and neoplasia and/or intestinal metaplasia and completed the treatment phase in 53 cases (32%),” they wrote. The investigators found that 157 patients (95%) achieved complete elimination of neoplasia, 137 (83%) achieved complete elimination of intestinal metaplasia and 19 (11%) achieved only complete elimination of dysplasia. Of the 137 patients who achieved complete elimination of intestinal metaplasia, recurrent intestinal metaplasia was observed in 48 patients (35%) and dysplasia was observed in 12 (9%). Of the 19 patients who achieved only complete elimination of dysplasia,

‘One-third of the patients in follow-up had recurrence of intestinal metaplasia. This high rate of recurrence warrants close surveillance. Recurrence was also noted as far out as 83 months, suggesting that surveillance should be continued indefinitely.’ —Vani Konda, MD recurrent dysplasia was observed in six patients (32%). Treatment failed to achieve complete eradication of dysplasia in eight patients (4.8%). Three patients had persistent HGD after 23, 35 and 50 months, respectively. Among all 176 patients who were initially identified, adverse events, such as dysphagia, perforation and stenosis, occurred in 42 patients (23.9%), including stricture in 21 patients (11.9%) and one treatmentrelated death. In multivariable and univariable analyses, the investigators found that multifocal dysplasia and age were risk factors for recurrence of dysplasia and/or carcinoma. The univariable analysis revealed that complete elimination of intestinal metaplasia was protective against recurrence.

High Rate of Recurrence The investigators noted that the strength of their study was the “long follow-up” period that allowed them to identify recurrence of intestinal metaplasia, “even long after complete eradication [of it] had been achieved.” They concluded that although multimodal endoluminal therapy for BE with HGD or early cancer was successful with regard to “complete eradication of all intestinal metaplasia,” the recurrence of intestinal metaplasia in one-third of cases “supports continued endoscopic surveillance, even after complete eradication.” Noting that recurrence was observed as late as 83 months after the end of initial treatment, the authors supported “the need for life-long surveillance and compliance with surveillance endoscopy in patients undergoing endoluminal therapy for dysplastic BE.” Dr. Konda acknowledged that “the study does report a relatively long follow-up period of a mean of 33 months,

and captures a notable number of recurrences.” She also noted that data from this study corroborate that multifocal dysplasia is a characteristic that is associated with a higher risk for recurrence, and that identifying risk factors associated with recurrence may allow physicians to tailor surveillance intervals for patients. Frederick L. Greene, MD, clinical professor of surgery at the University of North Carolina at Chapel Hill, who was not involved in the study, expressed concern about the rates of recurrence reported in this study. “The percentages of recurrence are of concern, [which is why] we must make sure that patients are screened aggressively. You can’t assume that the neoplastic tissue is completely gone after [this] treatment,” Dr. Greene said. “The intestinal metaplasia may have persisted or recurred because these patients had [gastroesophageal reflux] and were continuing to reflux.” He added: “It surprises me that the authors made no mention of the role of anti-reflux surgical procedures in this population. The key, if you’re going to do a study like this, is that it should be discussed in a multidisciplinary format, including surgical management, similar to the paradigm that’s been developed for the treatment of cancer. If the study is going to be more widely disseminated, more input from surgeons is needed.” Despite its shortcomings, Dr. Konda said the study confirms that endoscopic therapy can successfully eradicate HGD and/or intramucosal cancer, and supports a shift toward endoscopic therapy. “The data support the paradigm shift toward utilizing endoscopic therapy to treat HGD/intramucosal cancer in Barrett’s esophagus,” Dr. Konda said. ■


14

EXPERT ROUNDTABLE

GA GAS GAST ASTROEN ROENTER ROEN R T ERO LOGY TE Y & E NDOSCO COP OPY NEW EWS • AU AUGU A U ST 2 013 01

Maria T. Abreu, MD

Premysl Bercik, MD

Lawrence J. Brandt, MD

Chief and Mart artin n Kaiser K Chair Division of Gastroenterology Gas Professo sor or of Medicine Profes essor of Microbiology and ess Im Immunology University of Miami Miller School of Medicine Miami iami, Florida

Assistant Professor Division of Gastroenterology Department of Medicine McMaster University Medical Center Hamilton, Ontario

Professor of Medicin ine in ne and Surgery Albert Einstein College ge e of Medicine Emeritus Chief Division of Gastroentero ology Montefiore Medical Cen nter New York, New York

R. Balfour Sartor, MD

Gary Wu, MD

Distinguished Prrofesssor Departments of Medic cine (Gastroenterology an nd Hep patology) and Microbiology and Immunology University of North Ca arolina School of Me edicine e at Chapel Hill Chapel Hill, Nortth Carrolina Chape

[photo not available] Professor of Medicine Division of Gastroenterology University of Pennsylvania Perelman School of M Medicine Philadelphia, Pennsylvania

Expert Roundtable continued from page 1

Bacteria and the Pathogenes sis of IBD Maria T. Abreu, MD GEN: You have a specific interest in the role of bacteria in the pathogenesis of inflammatory bowel disease (IBD). How do you understand the relationship?

that are now part of our Western diet, have on the gut microbial population. There’s epidemiologic data that shows countries with the highest prevalence of IBD also are those with a Westernized diet (Molodecky NA et al. Gastroenterologyy 2012;142:46-54).

GEN: What role will microbiome manipulation play in clinical practice? Dr. Abreu: I suspect that once we have a better understanding of which bacteria are beneficial or harmful in the setting of IBD, we will be screening for these and manipulating them with prebiotics and probiotics. We know that the presence of Faecalibacterium prausnitziii is protective against recurrence of CD after ileal resection (Sokol H et al. Proc Natl Acad Sci USA A 2008;105:16731-16376). In this example, providing this bacterium may be an effective way to prevent recurrence, although it’s unlikely to be so simple.

Dr. Abreu: I think it’s plausible that there is ‘Genetic components are an essential a strain of bacteria that takes advantage of innate element in IBD pathogenesis, but it immune defects that are characteristic of IBD to cause a chronic infection. The density of the bacis my feeling that gut bacteria play at teria that we have to coexist with and our body’s least an equal, if not greater role.’ ability to keep these under control is critical to the development of IBD. —Maria T. Abreu, MD One epidemiologic study identified an increased incidence of IBD in individuals exposed to Salmonella or Campylobacterr (Gradel KO et al. Gastroenterology I do think that we’re a bit far from that point, how2009;137:495-501). Another recent metagenomic ever. Most probiotics that are currently available have study found that groups of individuals with Crohn’s disease (CD) and ulcerative colitis shown an extremely modest effect. I think this speaks to us still needing to identify the (UC) and healthy controls have distinct microbial populations (Hotte NS et al. PLoS right bugs and to get them to the right places. ■ Onee 2012;7:e37932). Genetic components are an essential element in IBD pathogenesis, but it is my feelDr. Abreu reported no relevant conflicts of interest. ing that gut bacteria play at least an equal, if not greater role. Results from a study of monozygotic twins support this view. The study included siblings where one had UC and found that the microbiome was more similar in individuals with UC than between siblings, suggesting that the inflammatory pattern is linked to the microbiome rather than genetic similarities (Lepage P et al. Gastroenterology 2011;141:227-236). Premysl Bercik, MD

Bacteria and the Gut–Brain Axis

GEN: What factors might induce gut microbial dysbiosis and potentially set in motion the development of IBD? Dr. Abreu: It is my feeling that overexposure to antibiotics during childhood, sometimes when they are not necessarily required, plays a role. Conversely, it is conceivable that patients with IBD may somehow develop more infections in childhood. Another piece that we’re not really reconciling, but that I believe is important, is consumption of antibiotics through beef and poultry, the largest market for quinolones in the country. I think it may be possible that ingestion of even trace amounts of antibiotics over a long time could be problematic. However, we don’t know the answer to this. We also don’t know what effects the unnatural substrates included in processed foods,

GEN: What is your particular focus in the area of microbiome research? Dr. Bercik: As a clinical gastroenterologist, I have long recognized that many patients with chronic gastrointestinal (GI) disorders, such as IBD and irritable bowel syndrome (IBS), also have mood and psychiatric abnormalities. Recent findings that there are alterations in the gut bacteria of these patients has led me to develop a specific interest in researching the interaction between the gut bacteria, intestinal inflammation and psychiatric disorders. see Expert Roundtable, page 16


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GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2013

Expert Roundtable continued from page 14

GEN: Can you describe the relationship between these three variables? Dr. Bercik: In the setting of IBD, psychiatric comorbidities, most often depression and anxiety, occur in around 80% of patients during a flare-up and in about 30% during disease remission. Mood is certainly affected by the effects of IBD on quality of life, and there is evidence that gut inflammation, specifically through inflammatory cytokines, can alter brain function. An alternative hypothesis is that psychiatric illness can be related to the presence of abnormal bacteria.

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An alternative hypothesis is that psychiatric illness can be related to the presence of abnormal bacteria.’ —Premysl Bercik, MD

Mark Lyte, PhD, and his team proposed the idea that microbes can affect the central nervous system (CNS). They found that mice gavaged with the pathogenic bacteria Campylobacter jejunii developed anxiety-like behavior within a few hours postinfection (Lyte M et al. Physiol Behav v 1998;65:63-68). Because this occurred before any significant immune response, it is highly suggestive that gut–brain signaling occurred through nerves. Indeed, Lyte et al subsequently linked this abnormal behavior with activation of vagal nerve pathways.

GEN: What are you finding in your own work? Dr. Bercik: Our group has demonstrated that altering the composition of gut microbiota in mice by administering nonabsorbable antimicrobials leads to a change in behavior and brain biochemistry (Bercik P et al. Gastroenterologyy 2011;141:599-609). Also, we have shown that colonizing mice with specific groups of bacteria can determine a certain behavioral phenotype. For instance, we administered the probiotic Bifidobacterium longum NCC3001 in mice with colitis who also demonstrated anxiety-like behavior to see if we could reduce inflammation (Bercik P et al. Neurogastroenterol Motil 2011;23:1132-1139). To our surprise, the probiotic did not affect colitis but worked as a very potent anxiolytic, suggesting that this specific bacterial strain interacts with the CNS through mechanisms unrelated to the immune system. Most of our research has been in animal models but we are using theories generated in these trials and translating them to clinical trials. We are now conducting a trial in patients with IBS and comorbid anxiety and depression to determine whether this specific probiotic has a similar anxiolytic effect in humans.

GEN: How close are these findings to clinical application? Dr. Bercik: We still need to identify specific healthy intestinal microbial populations and understand how they induce their beneficial effects, and this includes the effects of probiotics. We may be able in the future to scan a patient’s microbiota and determine what strains of bacteria are missing, or which ones are in excess. Then we can elaborate therapeutic approaches based on probiotics, antibiotics or diets that would shape the gut microbiota. ■ Dr. Bercik has received research support from Nestle Switzerland and is on the advisory board of Forest Laboratories and Janssen Canada.

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Fecal Microbiota Transplantation Lawrence J. Brandt, MD GEN: Fecal microbiota transplantation (FMT) has received a lot of press recently for the treatment of Clostridium difficile infection. What other indications could it potentially be used for?


EXPERT ROUNDTABLE

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2013

Dr. Brandt: Indeed, the strongest evidence we have for use of FMT is in patients with recurrent C. difficile infection where cure rates as high as 92% are reported (Gough E et al. Clin Infect Diss 2011;53:994-1002). I’ve conducted FMT in 22 patients with refractory UC and presented outcomes for eight of them at the 2012 American College of Gastroenterology meeting (abstract P403). Seven of eight patients experienced clinical improvements, but those with concomitant C. difficilee infection or UC following antibiotic use experienced the greatest benefits. With regard to CD, a single case report found a previously refractory patient was able to discontinue medications within three days after FMT but relapsed after 18 months (Borody TJ et al. Med J Austt 1989;150:604). I have treated five patients with CD and noticed transient clinical improvement in a minority. In a case series of 55 patients with IBS and IBD treated with FMT, 36% experienced cure, 16% had decreased symptoms and 47% had no response (Borody TJ et al. Med J Austt 1989;150:604). In another series, 45 patients with chronic constipation were treated with colonoscopic FMT and subsequent FMT by enema, and 89% reported symptom relief immediately after the procedure (Borody TJ et al. Probiotics, Prebiotics and New Foods Conference, Universita Urbaniana, Rome; Sept. 2-4, 2001).

NEW

17

period, but there was no direct evidence of an association with FMT (Brandt LJ et al. Am J Gastroenteroll 2012;107:1079-1087). Regardless, FMT must be performed with caution, as changing the intestinal microbiota may predispose the recipient to developing diseases the donor might also develop. The problem is that we are just beginning to learn about the relationship between intestinal microbiota, health and disease.

GEN: Is there an agreed-upon protocol for FMT? Dr. Brandt: No, but we are getting very close. A small working group published an agreed-upon protocol several years ago (Bakken JS et al. Clin Gastroenterol Hepatol 2011;9:1044-1049). Testing donor stool to ensure it is free of communicable pathogens is critical. Other see Expert Roundtable, page 18

In bowel preparation

The NEW Combination Makes the Difference Introducing Suclear

‘Case series and small case reports suggest

Provides the flexibility and convenience of two dosing regimens (same-day, split-dose), with success* achieved in 90% of patients1,2

FMT might be useful in

Significantly more “excellent” preps* with Suclear vs HalfLytely (47.7% vs 35.6%, respectively; P=0.01†) in same-day dosing comparison1

treating obesity, multiple sclerosis, insulin

– Prep time was 33% less with Suclear compared to HalfLytely (3.7 hours vs 5.5 hours, respectively; P<0.001†)1

resistance, idiopathic thrombocytopenic purpura, chronic fatigue

Equivalent rates of excellent cleansing* between Suclear and MoviPrep®‡ (51.9% vs 51.4%, respectively) in split-dose comparison1

syndrome and autism.’ —Lawrence J. Brandt, MD

Cecum reached in almost all patients using Suclear (split-dosing: 100%; same-day dosing: 99%)1

Overall, however, results are too limited to make any recommendations about the potential therapeutic role of FMT for IBS and IBD. Additionally, case series and small case reports suggest FMT might be useful in treating obesity, multiple sclerosis, insulin resistance, idiopathic thrombocytopenic purpura, chronic fatigue syndrome and autism (Aroniadias OC, Brandt LJ. Curr Opin Gastroenteroll 2013;29:79-84).

GEN: What safety concerns are there with the procedure? Dr. Brandt: Gastrointestinal adverse events are common but mild and short-lived. In one long-term follow-up study of 77 patients with C. difficilee infection treated with FMT, four developed an autoimmune disease in the 17-month follow-up

* *Based on investigator grading. † Statistically significant difference. ‡ MoviPrep [PEG-3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate and ascorbic acid for oral solution] is a trademark of the Norgine group of companies.

IMPORTANT SAFETY INFORMATION Suclear™ (sodium sulfate, potassium sulfate and magnesium sulfate oral solution; and PEG-3350, sodium chloride, sodium bicarbonate and potassium chloride for oral solution) is a combination of osmotic laxatives indicated for cleansing of the colon as a preparation for colonoscopy in adults. Most common adverse reactions (>2%) are overall discomfort, abdominal distention, abdominal pain, nausea, vomiting and headache. Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergies to components of Suclear. Use caution when prescribing for patients with a history of seizures, arrhythmias, impaired gag reflex, regurgitation or aspiration, impaired renal function or patients taking medications that may affect renal function or electrolytes. Patients with severe active ulcerative colitis may be at increased risk of exacerbation of their disease. Administration of osmotic laxative products may produce mucosal aphthous ulcerations, and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Patients with impaired water handling who experience severe vomiting should be closely monitored including measurement of electrolytes. Advise all patients to hydrate adequately before, during, and after use. Each bottle must be diluted with water to the recommended (sodium sulfate, potassium sulfate, and magnesium sulfate final volume.

NEW

Please see brief summary of Full Prescribing Information on adjacent page.

oral solution; and PEG-3350, sodium chloride, sodium bicarbonate and potassium chloride for oral solution)


18

EXPERT ROUNDTABLE

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2013

Host-Immune Interactions

Expert Roundtable continued from page 17

R. Balfour Sartor, MD

exclusion criteria are recent use of antibiotics, immunosuppressive or chemotherapeutic agents; illicit drug use; recent travel to areas where diarrhea is endemic; morbid obesity; or severe atopy.

Dr. Sartor: My interest is in host-immune interactions with intestinal bacteria, with specific applications to IBD.

GEN: Do you foresee FMT entering into the gastroenterologist’s clinical armamentarium in the near future? Dr. Brandt: Perhaps not in the near future but ultimately, yes.

GEN: Can you tell our readers about your specific focus in microbiome research?

GEN: What are some important findings in this field?

Dr. Sartor: There have been huge leaps in our understanding of host-immune interactions in this area. We now have further evidence that components of the normal gut microbiome drive the chronic inflammatory response, which can culminate in IBD, and genetic regulation can strongly affect a host’s response to these bacteria. For example, autophagy-related genes can limit a host’s ability to kill bacteria in the intestinal lumen and following phagocytosis in macrophages (Rioux JD et al. Nat (sodium sulfate, potassium sulfate, and magnesium sulfate Genet 2007;39:596-604).

Dr. Brandt is on the speaker’s panel and has received research support from Optimer Pharmaceuticals, Inc.

NEW

oral solution; and PEG-3350, sodium chloride, sodium bicarbonate and potassium chloride for oral solution)

‘Each genetically defined host responds differently to different bacterial

Introducing Suclear

stimulation. So, there’s

The NEW combination for dosing flexibility

heterogeneity on the

High success rates in same-day and split-dose regimens1,2 Cecum reached in nearly 100% of patients1 Significantly less prep time compared to HalfLytely1

host response side and heterogeneity on the

References: 1. Data on file. Braintree Laboratories, Inc., Braintree, MA. 2. Suclear [package insert]. Braintree, MA: Braintree Laboratories, Inc; 2013.

BRIEF SUMMARY: Before prescribing, please see Full Prescribing Information and Medication Guide for Suclear™ (sodium sulfate, potassium sulfate and magnesium sulfate oral solution; and PEG-3350, sodium chloride, sodium bicarbonate and potassium chloride for oral solution). INDICATIONS AND USAGE: A combination of osmotic laxatives indicated for cleansing of the colon as a preparation for colonoscopy in adults. CONTRAINDICATIONS: Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergies to components of the kit. WARNINGS AND PRECAUTIONS: Suclear is a combination of osmotic laxatives indicated for cleansing of the colon as a preparation for colonoscopy in adults. Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergies to Suclear. Use caution when prescribing for patients with a history of seizures, arrhythmias, impaired gag reflex, regurgitation or aspiration, impaired renal function or patients taking medications that may affect renal function or electrolytes. Patients with severe active ulcerative colitis may be at increased risk of exacerbation of their disease. Pre-dose and post-colonoscopy ECG’s should be considered in patients at increased risk of serious cardiac arrhythmias. Administration of osmotic laxative products may produce mucosal aphthous ulcerations, and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Patients with impaired water handling who experience severe vomiting should be closely monitored including measurement of electrolytes. Advise all patients to hydrate adequately before, during, and after use. Each bottle must be diluted with water to the recommended final volume. Pregnancy: Pregnancy Category C. Animal reproduction studies have not been conducted. It is not known whether this product can cause fetal harm or can affect reproductive capacity. Pediatric Use: Safety and effectiveness in pediatric patients has not been established. Geriatric Use: Of the 362 patients who took Suclear in clinical trials, 90 (25%) were 65 years of age or older, while 29 (8%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between geriatric patients and younger subjects. DRUG INTERACTIONS: Oral medication administered within one hour of the start of administration of each Suclear dose may not be absorbed completely.y Concurrent use of stimulant laxatives and Suclear may increase the risk of mucosal ulcerations or ischemic colitis. ADVERSE REACTIONS: Most common adverse reactions (>2%) are overall discomfort, abdominal distention, abdominal pain, nausea, vomiting and headache. Oral Administration: Consume only clear liquids (no solid food or milk) and avoid alcohol on the day before colonoscopy until after completion of the colonoscopy. Split-Dose (2-Day) Regimen (Preferred Method): Dose 1 – Evening before the colonoscopy (10 to 12 hours prior to Dose 2): Dilute the 6 oz. oral solution by pouring the entire contents of the bottle into the 16 oz. mixing container and then filling the container with cool water to the fill line and mix. Drink the entire solution in the container. It is best to complete drinking the solution within 20 minutes. Refill the container and drink another 16 oz. of water over the next 2 hours, and another before going to bed. Dose 2 – Next morning on the day of colonoscopy (start at least 3 ½ hours prior to colonoscopy): Dissolve the powder of Dose 2 by adding water to the fill line on the jug. Shake jug until powder is dissolved. The solution can be used with or without the addition of a flavor pack. Using the 16 oz. container provided, drink all the solution in the jug at a rate of one 16 oz. container every 20 minutes. Complete drinking the solution at least 2 hours before the colonoscopy. Consume only clear liquids until 2 hours prior to colonoscopy. Day-Before (1-Day) Regimen (Alternative Method): On the evening before the colonoscopy: Dose 1 (begin at least 3 ½ hours prior to bedtime): Dilute the 6 oz. oral solution by pouring the entire contents of the bottle into the 16 oz. mixing container and then filling the container with cool water to the fill line and mix. Drink the entire solution in the container. It is best to complete drinking the solution within 20 minutes. Drink another 16 oz. of water over the next 2 hours. Dose 2 (approximately 2 hours after starting Dose 1): Dissolve the powder of Dose 2 by adding water to the fill line on the jug. Shake jug until powder is dissolved. The solution can be used with or without the addition of a flavor pack. Using the 16 oz. container provided, drink all the solution in the jug at a rate of one 16 oz. container every 20 minutes. Refill the container and drink another 16 oz. of water before going to bed. Consume only clear liquids until 2 hours prior to colonoscopy. STORAGE: Store at 20-25°C (68-77°F). Excursions permitted between 15-30°C (59-86°F). Rx only. Distributed by Braintree Laboratories, Inc. Braintree, MA 02185 For additional information, please call 1-800-874-6756 or visit www.braintreelabs.com ©2013 Braintree Laboratories, Inc.

SU-14168

March, 2013

bacterial side, which make the interactions complex and very interesting.’ —R. Balfour Sartor, MD

There is also a growing understanding that certain defined bacterial products and species can induce regulatory T-cell responses. For example, in a small clinical study, genetically modified Lactococcus lactiss bacteria were used as “factories” to produce interleukin (IL)-10, with anti-inflammatory effects (Braat H et al. Clin Gastroenterol Hepatoll 2006;4:754759). Certain Clostridium subsets also have been used to induce production of regulatory T cells, again predominantly through IL-10–secreting pathways (Atarashi K et al. Sciencee 2011;331:337-341). Ongoing work in our laboratory here has shown that intestinal bacteria, including Escherichia coli, also can induce IL-10 secretion of B lymphocytes. There also is evidence that each genetically defined host responds differently to different bacterial stimulation. So, there’s heterogeneity on the host response side and heterogeneity on the bacterial side, which make the interactions complex and very interesting.


EXPERT ROUNDTABLE

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2013

GEN: What are the clinical implications of these developments? Dr. Sartor: In principle, manipulating the microbiome could be a much more physiologic way of altering the immune response in IBD than is currently done using biologic therapies. In theory, this would have far fewer side effects and complications than occur with biologics. You don’t zap the immune response and open the door for infections in the process. This approach also could be much more inexpensive than biologics. My prediction is that microbiome manipulation will become a clinically accepted and important way of treating IBD over the next few years, although we’re not there yet. I think we’ll see targeted and tailored therapies being used for individuals based on their unique bacterial and genetic profile.

GEN: Can intestinal microbiome manipulation play a role in treating other diseases?

the effect of these diets on the gut microbiome and on clinical responses ‘We hope to gain insights in patients with CD, and to identify bacterial taxa that might be used as into which bacteria biomarkers of individuals who may may be beneficial or respond to these diets. Furthermore, deleterious in IBD.’ using the longitudinal nature of our study, we hope to gain insights —Gary Wu, MD into which bacteria may be beneficial or deleterious in IBD. If we understand how these defined formula diets work, we also might be able to make some broader speculations about the effects of diet in patients with IBD.

Dr. Sartor: Yes, there have been extraordinarily interesting studies where clinical phenotypes have been transferred in mice using fecal transplants. For example, in seminal work done by Jeffrey Gordon, MD, at Washington University School of Medicine, the transfer of microbiota from obese to lean mice resulted in weight gain in recipient mice (Turnbaugh PJ et al. Nature 2006;444:1027-1031). Following the work done by Gordon et al, another mouse study has demonstrated that metabolic syndrome also can be transferred with gut microbiota (Vijay-Kumar M et al. Science 2010:328;228-231). In principle, if we were to develop an antibiotic or probiotic cocktail (or a combination of the two) that affected the balance of beneficial and detrimental bacteria in IBD, that cocktail could be applied, with modifications, to these other conditions. ■ Dr. Sartor is an advisor to the North American Probiotic Council, which is sponsored by Dannon and Yakult.

Diet and the Microbiome Gary Wu, MD GEN: Can you describe your specific area of microbiome research? Dr. Wu: My major focus as it relates to gastrointestinal diseases is in understanding how diet might alter the form and function of the microbiome in a way that might benefit patients with IBD. The Penn Human Microbiome Project (HMP) group, of which I am a principal investigator, is conducting a longitudinal, prospective cohort study tracking the effects of elemental diets on the gut microbiome and CD activity. Defined formula diets are sometimes used as first-line treatment for CD and can induce and maintain remission, but the mechanism of action is unknown (Albenberg LG et al. Curr Opin Gastroenteroll 2012;28:314-320). We hope to find associations between

19

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Quality continued from page 1

A collaboration between the ASGE and the American College of Gastroenterology, the GI Quality Improvement Consortium Ltd (GIQuIC) is a data registry that allows participants who have established the required workflow and data collection processes to report the quality indicators for their practice and compare them with those of their peers. According to the program’s website, “physicians and facilities as a whole are able to objectively

compare their performance measures to other endoscopists and facilities across the country” (http://giquic.gi.org). Gastrointestinal Associates in Knoxville, Tenn., has implemented a quality and value program, the preliminary results of which suggest that adopting such a program indeed can improve quality, and ultimately the bottom line. However, as is often the case when adopting a new protocol or course of action, lessons learned by early adopters may help smooth the way for others. “The early adopters tend to work out

the kinks, then it gets easier for later groups,” Dr. Deas pointed out. Gastrointestinal Associates already had the necessary infrastructure—an electronic medical record (EMR) system and an endowriter compatible with their chosen registry—as well as a cultural mindset of acceptance and anticipation of the changing shape of health care reimbursement. “We know reimbursement will be tied to quality, and that quality will be rewarded through pay-for-performance [P4P],” said Bergein Overholt, MD, managing partner of Gastrointestinal Associates.

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Dr. Overholt, cofounder of the GI Roundtable, outlined four steps that his practice took as they implemented a quality and value program, negotiated with payors, responded to benchmarking data returned by GIQuIC, and ultimately reaped rewards from their efforts.

Step 1: Do the Homework and Lay the Groundwork First, Dr. Overholt said, acquire and implement the necessary equipment: an endowriter that is compatible with one of two registries—GIQuIC or the American Gastroenterological Association’s Digestive Health Outcomes Registry— and ideally, an EMR system. Then, identify and appoint the people who will champion the program. Designate staff members who are devoted to, and compensated for, working with the program. These people likely will include a registered nurse who knows how to handle and collect data, administrative support, and most crucially, a physician in the leadership role. “The physician leader is the person who will develop the quality agenda, drive the issue through the board, educate physicians and staff, deal with the adversities some physicians may feel about quality measures, and negotiate with third parties,” Dr. Overholt said. Also critical is an agreement on behalf of the board that setting up a quality and value program will be advantageous. “Your physician leader can use the board’s decision that the practice needs a quality and value program as leverage as he or she implements the program throughout the practice,” Dr. Overholt said. The program takes approximately one year to implement, and also requires money. “The practice needs to make a financial commitment to pay the physician leader and the nurse, to cover the cost of the registry and for administrative support,” Dr. Overholt said. “You can figure on $100,000 the first year to implement a true quality and value program.”

Step 2: Phase In the Program Physicians should choose two or three benchmarks to observe, and then begin monitoring and submitting benchmark data to the registry. Share the benchmark data with the physicians in the practice, and then continue to monitor and report data, Dr. Overholt recommended. “It’s not a complicated process,” said Dr. Deas. “It’s all part of doing the endoscopy report, making sure you’ve clicked on all the relevant measurements. But anytime you change the workflow, it can be like pushing a rock up a hill.” As with any other adaptation, there will be enthusiasts who quickly adjust, a cohort that’s more or less adaptable, and


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GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST T 2013

stragglers who resist the change or struggle with it. It’s not necessarily easy to predict who will fall into which category. “I think it’s more personality than agedriven. Some of the worst pushback we get is from some of the younger guys who insist they want to go back to paper,” said Dr. Deas, who himself quickly became an enthusiast about EMRs and other electronic tools. “We do not yet know the generation of physicians who have grown up [using] electronic systems, so a lot of us, even the younger ones, are still on a learning curve,” he said. Other practices may need to upgrade their infrastructure before being able to implement a quality and value program. For example, the Raleigh Endoscopy Center of Raleigh, N.C., had to upgrade their endoscopy writer to be compatible with GIQuIC. Furthermore, the center consists of 20 doctors and five practices, all with different EMR systems. “Our implementation ultimately required significantly more manual input than was ideal,” noted Michael Brody, MD, medical director of the center. “In an ideal situation, your systems would all be connected, so as soon as your pathology results come back, it’s all put directly into your endowriter and the data are all there. We had to have staff from the endoscopy center input our pathology results and follow up with the appropriate recommendations.” To streamline the process, the center upgraded its endowriter in February 2013. “We’d been collecting data since third quarter 2012, but didn’t have it fully integrated until a couple of months ago,” Dr. Brody said.

Step 3: Connect With Third Parties Discuss your participation in a quality and value program with payors, Dr. Overholt advised. “They may be surprised at this point to see physicians leading a P4P program, and they’ll be particularly interested if

your program lowers their cost and proves quality that they can show,” he said. In some cases, payors already are pushing for implementation of a recognized quality registry program. “We’d had robust quality assurance testing for our facility for 10 years, and when we put our benchmarks up against the national benchmarks, we exceeded them all,” Dr. Brody said. “But BlueCross BlueShield strongly wanted a recognized quality registry program, so we went with GIQuIC.”

Step 4: Negotiate With Third Parties Once the benchmarking program and relationships with payors have been established, Dr. Overholt suggested, “Use the tri-society colonoscopy benchmarks your practice has selected for negotiations on quality with the insurance company. Keep it simple: two, no more than three benchmarks.” The approach his practice used was to suggest to the payors that in the interest of improving quality and reducing cost, the group would exceed the national benchmarks by a certain percentage, using selected criteria, for a given percentage increase in reimbursement. “If you really want to stick your neck out, you can tell them, ‘If we don’t reach those goals, we will not require any additional payment,’ ” Dr. Overholt said. “I would urge you to say that only if you’re

Expert Roundtable continued from page 17

GEN: Apart from your own research, what are some other exciting findings in the field of diet–microbiome interactions? Dr. Wu: Two studies have yielded very important observations. Eugene Chang, MD, and his research group showed that a type of saturated milk-derived fat alters the microbiome of mice in a way that seems to accelerate the development of colitis (Devkota S et al. Naturee 2012;487:104-108). I think this is a very interesting observation and provides proof of principle that what you eat can alter the microbiome in a way that then influences intestinal inflammation. The other study looked at the effects of dietary phosphatidylcholine that delivers choline to the gut microbiota when consumed by mice (Wang Z et al. Naturee 2011;472:5763). That study showed that gut microbiota metabolized choline into a small molecule that accelerated the development of cardiovascular disease. In this case, we see that what

very confident about what you’re going to be doing.” Gastrointestinal Associates chose two benchmarks to report: a 10-year followup for an average-risk patient with a normal screening colonoscopy, and five-year follow-up for non–high-risk patients with fewer than three adenomas. At the time they implemented GIQuIC, the registry had collected data on about 100,000 cases, and had a compliance rate of 64% for the first metric and 57% for the second one. “So we went to our third party and said, ‘We’ll be better than that.’ ” Dr. Overholt’s group contracted for 70% compliance with the 10-year followup normal screening colonoscopy and 60% compliance for the five-year follow-up in patients with three or fewer adenomas. “That may seem a little low, but it gives you flexibility. We all see patients who just don’t fit the guidelines and are special situations,” Dr. Overholt explained. In the first quarter, after implementing their quality and value program, the practice found they had exceeded the contracted goal for the first metric: Their doctors achieved a compliance rate of 77%. For the second metric, however, they matched the national benchmark exactly, at 57%. “We did not meet our goal in our first quarter of operation,” said Dr. Overholt. “I took this data back to our group and showed it to the physicians. In the first two months of our next quarter, we saw a dramatic improvement in compliance

with that five-year follow-up.” Now that the practice will be receiving the raise they contracted for—a 3% increase in total payments—the physicians who helped to achieve that goal will be rewarded. “This is new money. It goes into a separate pile, and we will [divide] it up at the end of the year according to whether a physician reaches compliance with the benchmarks,” Dr. Overholt said. “If they reach it, they get their share of the bonus; if they don’t reach it, they get nothing.” The financial incentive for the Raleigh Endoscopy Center was a bit different. They negotiated with BlueCross BlueShield to bump all of their practices to tier 1 status if they participated in a recognized quality registry and were successful, which they were. “Although we have three centers all providing the same level of care and using the same techniques and quality assurance testing, one of our centers had tier 2 status for no discernible reason,” Dr. Brody said. “It was a dilemma that initially we didn’t know how to overcome, but [implementing GIQuIC] allowed us to do that by having a recognized quality registry.” Dr. Deas’ Fort Worth Endoscopy Center has not yet attempted to use its participation in GIQuIC for contracting, but he envisions that economic incentives will drive the uptake of national registry participation. “The adoption is improving, and I think some of the incentives Dr. Overholt captured in his talk will drive more adoption,” he said. “Some of that [incentive] may come from Medicare, where we’ll be reporting quality measures via a registry, and GIQuIC will be a very efficient way to do that. Also, the PQRS [Physician Quality Reporting System] used to be a 1% to 2% bonus if you were reporting it, but that will turn into a penalty if you’re not reporting it in 2014. So, registry reporting will be financially beneficial as well as doing the right ■ thing,” Dr. Deas said.

you eat can deliver a substrate to the microbiota, which then produce small molecules that influence disease development. If we understand what these small molecules and related signaling pathways are, we might gain new insights into the pathogenesis of IBD and identify new therapeutic targets.

GEN: What role do you see diet playing in the future in management of GI diseases? Dr. Wu: With IBD in particular, the hope is that studying how dietary interventions regulate the gut microbiome composition and what effect the microbiome has in patients with IBD will give us a better idea of what a healthy diet for these patients might be. Despite what we know about the effects of diet on the microbiota, there’s still a lot we don’t know. Further studies are needed to identify the mechanisms by which diet alters the gut microbiome in a way that influences human health in a meaningful way. ■ Dr. Wu reported no relevant conflicts of interest.


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Experts’ Picks:

Top Liver Abstracts From EASL and COMPILED AND WRITTEN BY DAVID WILD

Keeping up with the many exciting advances in the management of liver diseases is a difficult task. Gastroenterology & Endoscopy News asked three expert hepatologists to share re their opinions of the top liver abstracts from The International Liver Congress 2013/ European Association for the Study of the Liver (EASL) and the 2013 Digestive Disease Week (DDW) meeting. Following are their selections and insights.

Patrick Basu, MD Assistant Clinical Professor Department of Digestive and Liver Diseases Columbia University College of Physicians and Surgeons New York, New York Clinical Professor Hofstra North Shore-LIJ School of Medicine Hofstra University Hempstead, New York

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ofosbuvir + Peginterferon + Ribavirin for 12 Weeks Achieves 90% SVR12 in Genotype 1, 4, 5, or 6 HCV Infected Patients: The NEUTRINO Study (Lawitz E et al. EASL Abstract 1411)

non-cirrhotic patients with HCV GT1, 96% in HCV GT4 patients and 100% in HCV GT5/6 patients. GT Common adverse events (AEs) of treatmen nt included fatigue (59%), headache (36%), nau usea (34%) and insomnia (25%); 2% of patients discoontinued treatment. Serious AEs occurred in 1% off patients. Dr. Basu: This study looked at the efficacy of a single dose of the pangenomic HCV NS5B polymeraase nucleotide inhibitor, sofosbuvir, along with PEG-IFN and RBV, in patients with a range of HCV genotyp pes. These included patients with difficult-to-treat HCV GT1 and HCV GT4, as well as individuals with compen nsated cirrhosis. The SVR rates were impressive. Notablly, 80% of all patients with cirrhosis achieved SVR at weeek 12.

A

ll Oral Therapy With Sofosbuvir + Ribavirin for 12 or 16 Weeks in Treatment Experienced GT2/3 HCV-Infected Patients: Results of the Phase 3 FUSION Trial (Nelson DR et al. EASL Abstract 6)

This Phase III open-label study included 292 treatmentnaive patients with chronic hepatitis C virus (HCV) This randomized, placebo-controlled, double-blind genotype (GT) 1 infection, 28 patients with HCV GT4 Phase III study of dual therapy with sofosbuvir 400 infection and seven patients with HCV GT5/6 infec- mg daily and RBV 1,000 to 1,200 mg daily, included tion. All patients received sofosbuvir, a pangenomic 201 treatment-experienced patients with HCV GT2/3. NS5B HCV polymerase inhibitor, 400 mg daily, along Most of the patients were white men, with a mean age with ribavirin (RBV) 1,000 to of 54 years. Thirty per1,200 mg daily and pegylated cent of patients had the interferon (PEG-IFN) 180 IL28B genotype CC, C mcg weekly, for 12 34% had compensated ‘The SVR rates were weeks. Seventeen cirrhosis, 63% had HCV impressive. Notably, 80% GT3, 75% had relapsed percent of patients had compensated cirrhosis following prior treatof all patients with cirrhosis and 29% had interleukin 28 B ment and 25% were prior achieved SVR at week 12.’ (IL28B) genotype CC. At basenull responders. Patients line, patients had greater than were randomized to —Patrick Basu, MD 90,000 platelets per mcL, none receive either 12 weeks had neutropenia and the mean of treatment with sofosHCV RNA viral load was 6.4 buvir and RBV followed log10 IU/mL. by four weeks of placebo, The researchers reported an overall sustained viro- or 16 weeks of treatment with sofosbuvir and RBV. logic response (SVR) rate of 90% at 12 weeks after In the 16-week treatment group, 78% of HCV treatment completion, a difference statistically higher GT2 patients with cirrhosis and 100% of HCV GT2 than the 60% reported in historical controls, they said. patients without cirrhosis achieved SVR compared All of the patients who did not achieve SVR at week with 60% and 96%, respectively, of patients in the 12 relapsed following an initial response to treatment. 12-week treatment group. SVR rates in HCV GT3 None of these patients were found to have NS5B S282T patients in the 16-week treatment group were 61% and resistance after relapse. 63% for patients with or without cirrhosis, respectively, Subgroup-specific SVR rates at week 12 were compared with 19% and 37%, respectively, of patients 80% in patients with cirrhosis, 89% in cirrhotic and in the 12-week treatment group.

Serious AEs occurred in 3% and 5% of patients in the 16- and 12-week treatment groups, respectively, but no patients discontinued treatment because of drug-related AEs. Of patients in the 1616 and 12-week 12 week groups, 10% and 5%, respectively, experienced a drop in hemoglobin greater than 10 g/dL, and 2% of patients in the 12-week treatment group had hemoglobin less than 8.5 g/dL. Common AEs in both treatment groups included fatigue, headache, insomnia, nausea, irritability, cough and diarrhea. Dr. Basu: This trial looked at an interferon (IFN)free regimen, including another pangenomic drug with no associated resistance to RBV. The study population again included very difficult-to-treat patients, including prior relapsers and null responders, a large population of patients with HCV GT3 and a significant number of patients with cirrhosis. The results indicate that this treatment regimen should be used in patients with HCV GT3, and extended to 16 weeks.

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elaprevir With Adjusted Dose of Ribavirin in Naive CHC-G1: Efficacy and Treatment in CHC in Hemodialysis Population. Target C Trial—A Placebo Randomized Control Clinical Trial (Basu P et al. DDW Abstract 517)

This randomized, placebo-controlled trial included 36 treatment-naive patients with chronic HCV GT1 undergoing hemodialysis. Twelve patients were assigned to receive telaprevir 750 mg (three tablets twice daily on the day of dialysis, and two tablets three times daily post-dialysis) along with PEG-IFN 135 mcg once weekly and RBV 200 mg three times weekly and for 12 weeks, followed by an additional 12 weeks of treatment with PEG-IFN and RBV. Another 12 patients received the same dose of telaprevir along with PEG-IFN plus a placebo for 12 weeks, followed


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by treatment with PEG-IFN and RBV for an additional 24 weeks. A third group of 12 patients underwent treatment with PEG-IFN and RBV plus a placebo for 24 weeks, followed by a 12-week treatment pause and resumption of the same regimen between weeks 36 and 48. Fortythree percent of patients had HCV GT1a, 64% were black, 29% had IL28B genotype CC, C 26% had IL28B genotype TT T and 46% had IL28B genotype CT. T Rapid virologic response (RVR) occurred in 50% of patients in the telaprevir 24-week total treatment group, in 42% of patients in the telaprevir 36-week total treatment group and in 25% of placebo recipients. SVR rates at week 24 were 63%, 50% and 25% in the three groups, respectively. One patient each in the 24-week telaprevir treatment group and the placebo group experienced viral breakthrough. Both patients were black, had HCV GT1a and IL28B genotype TT. T Thrombocytopenia, neutropenia, anemia, anorectal dysfunction, dysgeusia, depression and constipation were more common among patients who took telaprevir. Dr. Basu: The patients included in this study were at high risk for transplantation, given that they had accelerated fibrosis (14%, F2; 72%, F3; 14%, F4) and that patients on hemodialysis have historically low SVR rates. Moreover, posttransplantation resumption of accelerated fibrosis is common, and 1.56% of hemodialysis patients with HCV experience graft failure after transplantation. We hypothesized that if we could optimize the dosing regimen of telaprevir—a drug that does not undergo renal metabolism and is therefore safe for patients on hemodialysis—we might be able to increase SVR rates. After reviewing the literature, we found an interesting telaprevir dosing regimen: On the day of dialysis, patients are administered three tablets twice daily, and on the day after hemodialysis, they are given two tablets three times daily. With our adjusted dosing schedule, we achieved higher SVR rates compared with the traditional standard of care in hemodialysis patients with HCV GT1. The extended 48-week treatment regimen showed no added benefit. We are now conducting a large, prospective trial to validate the findings. ■ Dr. Basu has received financial support from Bristol-Myers Squibb, Genentech, Gilead Sciences, Ironwood Pharmaceuticals, Merck & Co., Otsuka Pharmaceutical Co., Ltd., Salix Pharmaceuticals, Takeda Pharmaceuticals, Three Rivers Pharmaceuticals and Vertex Pharmaceuticals.

Jordan Feld, MD, MPH Assistant Professor of Medicine University of Toronto Toronto, Canada Staff Hepatologist Division of Gastroenterology Department of Medicine Toronto Western Hospital Toronto, Canada

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ll-Oral Sofosbuvir-Based 12-Week Regimens for the Treatment of Chronic HCV Infection: The ELECTRON Study (Gane EJ et al. EASL Abstract 14) Investigators set out to determine whether combining sofosbuvir, a uridine nucleotide analog HCV polymerase inhibitor, and a second direct-acting antiviral agent with a different mechanism of action, could improve SVR rates when administered with RBV in patients with HCV GT1. To this end, they evaluated

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sofosbuvir 400 mg once daily plus RBV 1,000 to 1,200 mg in 25 treatment-naive patients and 10 prior null responders with HCV GT1; two other groups of similar numbers of patients received the same treatment regimen plus either ledipasvir (GS-5885), an HCV NS5A inhibitor, 90 mg daily, or GS-9669, a non-nucleotide NS5B inhibitor, 500 mg daily. Treatment duration in all groups was 12 weeks. Mean baseline HCV RNA levels ranged from 5.9 log10 to 6.9 log10. None of the patients see Top Liver, page 24

For overt HE* patients

OUT OF THE HOSPITAL DOESN’T MEAN OUT OF THE WOODS “After an episode of [overt HE], prophylactic therapy with lactulose or rifaximin is recommended for an indefinite period of time or until liver transplantation.” —Clinics in Liver Disease, February 20121 73% of recurrences among lactulose patients result in hospitalization 2 Xifaxan 550 mg reduces the risk of HE-related hospitalizations by 50%3†‡ The most common adverse reactions (≥12% incidence) in clinical trials with Xifaxan 550 mg were peripheral edema, nausea, dizziness, and fatigue.

Prescribe. Protect. Repeat.

*HE=hepatic encephalopathy. † Over a 6-month period; P=0.0129 vs placebo.3 ‡ HE-related hospitalization defined as hospitalization directly caused by HE or a hospitalization during which an HE event occurred.3

Important Safety Information About XIFAXAN 550 mg XIFAXAN® (rifaximin) 550 mg tablets are contraindicated in patients with a hypersensitivity to rifaximin, any of the rifamycin antimicrobial agents, or any of the components in XIFA X AN. Hypersensitivity reactions have included exfoliative dermatitis, angioneurotic edema, and anaphylaxis. Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XIFAXAN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon which may lead to overgrowth of C. difficile. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. There is increased systemic exposure in patients with more severe hepatic dysfunction. The clinical trials were limited to patients with MELD scores <25. Therefore, caution should be exercised when administering XIFAXAN to patients with severe hepatic impairment (Child-Pugh C).

Based on animal data, XIFAXAN may cause fetal harm. Discontinue in nursing mothers after taking into account the importance of the drug to the mother. The most common adverse reactions occurring in ≥10% of patients and at a higher incidence than placebo in the clinical study were edema peripheral (15%), nausea (14%), dizziness (13%), fatigue (12%), and ascites (11%). Xifaxan 550 mg is not available for sale outside the U.S. Xifaxan 550 mg is licensed by Alfa Wassermann S.p.A. to Salix Pharmaceuticals, Inc. Please see Brief Summary on reverse. References: 1. Khungar V, Poordad F. Management of overt hepatic encephalopathy. Clin Liver Dis. 2012;16(1):73-89. 2. Bajaj JS, Sanyal AJ, Bell D, Gilles H, Heuman DM. Predictors of the recurrence of hepatic encephalopathy in lactulose-treated patients. Aliment Pharmacol Ther. 2010;31(9):10121017. 3. Xifaxan [prescribing information]. Raleigh, NC: Salix Pharmaceuticals, Inc; 2011.

Web site: www.salix.com 8510 Colonnade Center Drive, Raleigh, NC 27615 Tel. 866-669-SLXP (7597) ©2012 Salix Pharmaceuticals, Inc. All rights reserved. Printed in USA. RIFHE 12/74-1

www.Xifaxan550.com


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Top Liver continued from page 23

had cirrhosis, and most had HCV GT1a. In the control group, 84% and 10% of treatment-naive and null responders, respectively, achieved SVR at week 12. In the ledipasvir treatment group, 100% of patients achieved SVR at week 12. In the GS-9669 group, 92% of treatment-naive patients achieved SVR at week 12, and among three prior null responders with data available at week 12 post-treatment, all achieved SVR.

Serious AEs occurred in one treatment-naive patient in the control group and in two treatment-naive patients who received ledipasvir. Dr. Feld: Recognizing the caveats that this was a small trial in very healthy patients without cirrhosis, these data look very impressive and both combinations of treatments look extremely promising. The addition of ledipasvir seemed to overcome

the issue of relapse seen in patients treated with sofosbuvir and ribavirin alone, particularly in prior null responders. For patients treated with 12 weeks of sofosbuvir and ribavirin, only 1 of 10 prior null responders achieved SVR. With the addition of ledipasvir, all prior null responders achieved SVR at week 12. Sofosbuvir and ledipasvir have been combined into one pill, which taken once

‘The addition of ledipasvir seemed to overcome the issue of relapse seen in patients treated with sofosbuvir and ribavirin alone, particularly in prior null responders.’ —Jordan Feld, MD, MPH

The following is a brief summary; see complete Prescribing Information at www.Xifaxan550.com.

INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of XIFAXAN and other antibacterial drugs, XIFAXAN when used to treat infection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

had a mean age of 56.26 (range: 21-82) years; approximately 20% of the patients were ≥ 65 years old, 61% were male, 86% were White, and 4% were Black. Ninety-one percent of patients in the trial were taking lactulose concomitantly. All adverse reactions that occurred at an incidence ≥ 5% and at a higher incidence in XIFAXAN 550 mg-treated subjects than in the placebo group in the 6-month trial are provided in Table 2. (These include adverse events that may be attributable to the underlying disease).

Table 1: Adverse Reactions Occurring in ≥ 5% of Patients Receiving XIFAXAN and at a Higher Incidence Than Placebo

Hepatic Encephalopathy XIFAXAN 550 mg is indicated for reduction in risk of overt hepatic encephalopathy (HE) recurrence in patients ≥ 18 years of age. In the trials of XIFAXAN for HE, 91% of the patients were using lactulose concomitantly. Differences in the treatment effect of those patients not using lactulose concomitantly could not be assessed. XIFAXAN has not been studied in patients with MELD (Model for End-Stage Liver Disease) scores > 25, and only 8.6% of patients in the controlled trial had MELD scores over 19. There is increased systemic exposure in patients with more severe hepatic dysfunction [see Warnings and Precautions (5.4), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

CONTRAINDICATIONS Hypersensitivity XIFAXAN is contraindicated in patients with a hypersensitivity to rifaximin, any of the rifamycin antimicrobial agents, or any of the components in XIFAXAN. Hypersensitivity reactions have included exfoliative dermatitis, angioneurotic edema, and anaphylaxis [see Adverse Reactions (6.2)].

WARNINGS AND PRECAUTIONS Travelers’ Diarrhea Not Caused by Escherichia coli XIFAXAN was not found to be effective in patients with diarrhea complicated by fever and/or blood in the stool or diarrhea due to pathogens other than Escherichia coli. Discontinue XIFAXAN if diarrhea symptoms get worse or persist more than 24-48 hours and alternative antibiotic therapy should be considered. XIFAXAN is not effective in cases of travelers’ diarrhea due to Campylobacter jejuni. The effectiveness of XIFAXAN in travelers’ diarrhea caused by Shigella spp. and Salmonella spp. has not been proven. XIFAXAN should not be used in patients where Campylobacter jejuni, Shigella spp., or Salmonella spp. may be suspected as causative pathogens.

Clostridium difficile-Associated Diarrhea Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XIFAXAN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon which may lead to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Development of Drug Resistant Bacteria Prescribing XIFAXAN for travelers’ diarrhea in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Severe (Child-Pugh C) Hepatic Impairment There is increased systemic exposure in patients with severe hepatic impairment. Animal toxicity studies did not achieve systemic exposures that were seen in patients with severe hepatic impairment. The clinical trials were limited to patients with MELD scores <25. Therefore, caution should be exercised when administering XIFAXAN to patients with severe hepatic impairment (Child-Pugh C) [see Use in Specific Populations (8.7), Nonclinical Toxicology (13.2) and Clinical Studies (14.2)].

ADVERSE REACTIONS Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Hepatic Encephalopathy The data described below reflect exposure to XIFAXAN 550 mg in 348 patients, including 265 exposed for 6 months and 202 exposed for more than a year (mean exposure was 364 days). The safety of XIFAXAN 550 mg taken two times a day for reducing the risk of overt hepatic encephalopathy recurrence in adult patients was evaluated in a 6-month placebo-controlled clinical trial (n = 140) and in a long term follow-up study (n = 280). The population studied

Number (%) of Patients

MedDRA Preferred Term Edema peripheral Nausea Dizziness Fatigue Ascites Muscle spasms Pruritus Abdominal pain Abdominal distension Anemia Cough Depression Insomnia Nasopharyngitis Abdominal pain upper Arthralgia Back pain Constipation Dyspnea Pyrexia Rash

XIFAXAN Tablets 550 mg TWICE DAILY N = 140

Placebo N = 159

21 (15%) 20 (14%) 18 (13%) 17 (12%) 16 (11%) 13 (9%) 13 (9%) 12 (9%) 11 (8%) 11 (8%) 10 (7%) 10 (7%) 10 (7%) 10 (7%) 9 (6%) 9 (6%) 9 (6%) 9 (6%) 9 (6%) 9 (6%) 7 (5%)

13 (8%) 21 (13%) 13 (8%) 18 (11%) 15 (9%) 11 (7%) 10 (6%) 13 (8%) 12 (8%) 6 (4%) 11 (7%) 8 (5%) 11 (7%) 10 (6%) 8 (5%) 4 (3%) 10 (6%) 10 (6%) 7 (4%) 5 (3%) 6 (4%)

The following adverse reactions, presented by body system, have also been reported in the placebo-controlled clinical trial in greater than 2% but less than 5% of patients taking XIFAXAN 550 mg taken orally two times a day for hepatic encephalopathy. The following includes adverse events occurring at a greater incidence than placebo, regardless of causal relationship to drug exposure. Ear and Labyrinth Disorders: Vertigo Gastrointestinal Disorders: Abdominal pain lower, abdominal tenderness, dry mouth, esophageal variceal bleed, stomach discomfort General Disorders and Administration Site Conditions: Chest pain, generalized edema, influenza like illness, pain NOS Infections and Infestations: Cellulitis, pneumonia, rhinitis, upper respiratory tract infection NOS Injury, Poisoning and Procedural Complications: Contusion, fall, procedural pain Investigations: Weight increased Metabolic and Nutritional Disorders: Anorexia, dehydration, hyperglycemia, hyperkalemia, hypoglycemia, hyponatremia Musculoskeletal, Connective Tissue, and Bone Disorders: Myalgia, pain in extremity Nervous System Disorders: Amnesia, disturbance in attention, hypoesthesia, memory impairment, tremor Psychiatric Disorders: Confusional state Respiratory, Thoracic, and Mediastinal Disorders: Epistaxis Vascular Disorders: Hypotension

Postmarketing Experience The following adverse reactions have been identified during post approval use of XIFAXAN. Because these reactions are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to either their seriousness, frequency of reporting or causal connection to XIFAXAN. Infections and Infestations Cases of C. difficile-associated colitis have been reported [see Warnings and Precautions (5.2)]. General Hypersensitivity reactions, including exfoliative dermatitis, rash, angioneurotic edema (swelling of face and tongue and difficulty swallowing), urticaria, flushing, pruritus and anaphylaxis have been reported. These events occurred as early as within 15 minutes of drug administration.

DRUG INTERACTIONS In vitro studies have shown that rifaximin did not inhibit cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and CYP3A4 at concentrations ranging from 2 to 200 ng/mL [see Clinical Pharmacology (12.3)]. Rifaximin is not expected to inhibit these enzymes in clinical use.

An in vitro study has suggested that rifaximin induces CYP3A4 [see Clinical Pharmacology (12.3)]. However, in patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations. An in vitro study suggested that rifaximin is a substrate of P-glycoprotein. It is unknown whether concomitant drugs that inhibit P-glycoprotein can increase the systemic exposure of rifaximin [see Clinical Pharmacology (12.3)].

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy g y Category g yC There are no adequate and well controlled studies in pregnant women. Rifaximin has been shown to be teratogenic in rats and rabbits at doses that caused maternal toxicity. XIFAXAN tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Administration of rifaximin to pregnant rats and rabbits at dose levels that caused reduced body weight gain resulted in eye malformations in both rat and rabbit fetuses. Additional malformations were observed in fetal rabbits that included cleft palate, lumbar scoliosis, brachygnathia, interventricular septal defect, and large atrium. The fetal rat malformations were observed in a study of pregnant rats administered a high dose that resulted in 16 times the therapeutic dose to diarrheic patients or 1 times the therapeutic dose to patients with hepatic encephalopathy (based upon plasma AUC comparisons). Fetal rabbit malformations were observed from pregnant rabbits administered mid and high doses that resulted in 1 or 2 times the therapeutic dose to diarrheic patients, based upon plasma AUC comparisons. Post-natal developmental effects were not observed in rat pups from pregnant/lactating female rats dosed during the period from gestation to Day 20 post-partum at the highest dose which resulted in approximately 16 times the human therapeutic dose for travelers’ diarrhea (based upon AUCs) or approximately 1 times the AUCs derived from therapeutic doses to patients with hepatic encephalopathy.

Nursing Mothers It is not known whether rifaximin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from XIFAXAN, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use The safety and effectiveness of XIFAXAN 200 mg in pediatric patients with travelers’ diarrhea less than 12 years of age have not been established. The safety and effectiveness of XIFAXAN 550 mg for HE have not been established in patients < 18 years of age.

Geriatric Use Clinical studies with rifaximin 200 mg for travelers’ diarrhea did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger subjects. In the controlled trial with XIFAXAN 550 mg for hepatic encephalopathy, 19.4% were 65 and over, while 2.3% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Renal Impairment The pharmacokinetics of rifaximin in patients with impaired renal function has not been studied.

Hepatic Impairment Following administration of XIFAXAN 550 mg twice daily to patients with a history of hepatic encephalopathy, the systemic exposure (i.e., AUC␶) of rifaximin was about 10-, 13-, and 20-fold higher in those patients with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, respectively, compared to that in healthy volunteers. No dosage adjustment is recommended because rifaximin is presumably acting locally. Nonetheless, caution should be exercised when XIFAXAN is administered to patients with severe hepatic impairment [see Warnings and Precautions (5.4), Clinical Pharmacology (12.3), Nonclinical Toxicology (13.2), and Clinical Studies (14.2)]. Manufactured for Salix Pharmaceuticals, Inc., Raleigh, NC 27615, under license from Alfa Wassermann S.p.A. XIFAXAN® is a trademark of Salix Pharmaceuticals, Inc., under license from Alfa Wassermann S.p.A. Copyright © Salix Pharmaceuticals, Inc.

Web site: www.salix.com E-mail: customer.service@salix.com 8510 Colonnade Center Drive, Raleigh, NC 27615 Tel. 866-669-SLXP (7597) ©2012 Salix Pharmaceuticals, Inc. All rights reserved. Printed in USA. RIFHE 12/74

daily seems to be well tolerated and could improve compliance with medication. In future studies, it will be important to explore whether therapy can be shortened, and whether ribavirin can be eliminated, reducing the pill burden for patients and avoiding anemia. Eliminating ribavirin also would open the possibility of treating patients with renal failure or chronic anemia who cannot take ribavirin. Clearly, these combinations of treatments will have to be studied in larger, Phase III trials including more difficult-to-cure patients, particularly those with cirrhosis and other HCV genotypes, against which both ledipasvir and GS-9669 have demonstrated activity. If these results hold up, this all-oral HCV antiviral regimen will compare favorably to other IFN-free options for patients with HCV GT1.

S

VR12 Rates and Safety of Triple Therapy Including Telaprevir or Boceprevir in 221 Cirrhotic Non Responders Treated in the French Early Access Program (ANRS CO20-CUPIC) (Fontaine H et al. EASL Abstract 60) As part of the French Early Access Program, 485 treatment-experienced HCV GT1a/b patients with cirrhosis were offered treatment with a first-generation HCV protease inhibitor (PI) in combination with PEG-IFN and RBV in an open-label fashion. The treating physicians decided whether to prescribe boceprevir- or telaprevir-based triple therapy: 190 individuals received the standard boceprevir-based regimen, and 295 patients underwent standard telaprevir-based treatment. The majority of patients were prior relapsers. All patients had cirrhosis, nearly all were Child-Pugh class A, and patients had a mean Model for End-stage Liver Disease score of 8.1. Findings of the intent-to-treat analysis showed that 79% of telaprevir recipients had a virologic response at week 8,


GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST AUGUST 2013 2013

and 40% continued with SVR at week 12: This included 53% of prior relapsers, 32% of partial responders and 29% of null responders. Among those who discontinued treatment early, approximately 19% did so because of detectable HCV RNA, 27% relapsed, 41% experienced viral breakthrough and 14% experienced AEs. In the boceprevir treatment group, 51% had a virologic response at week 8, and 41% continued with SVR at week 12, including 51% of prior relapsers, 40% of partial responders and 11% of null responders. Premature discontinuation of treatment in this group was due to detectable HCV RNA in approximately 36% of patients, relapse in 27%, viral breakthrough in 26% and AEs in 11%. Serious AEs occurred in 54% and 51% of telaprevir and boceprevir recipients, respectively, and included a 2.4% and 1.6% mortality rate, respectively. Grade 3/4 infections occurred in 9.1% and 4.2% of telaprevir and boceprevir recipients, respectively, grade 3/4 hepatic decompensation occurred in 5.1% and 4.7%, respectively, grade 3 rash occurred in 5.4% and 1%, respectively, and grade 3/4 anemia in 12.9% and 10%, respectively. Dr. Feld: The CUPIC (Compassionate Use of Protease Inhibitors in Cirrhotics) trial is a critical, real-world evaluation of two first-generation HCV PIs. The findings highlight the importance of conducting real-world studies to evaluate the true effectiveness and safety of approved regimens when their use expands beyond the highly selected trial populations. Previous reports have shown a high rate of AEs in this cohort of prior relapsers and nonresponders with cirrhosis. The final safety data are somewhat reassuring because the rate and severity of AEs was similar at full follow-up to rates reported at week 16, suggesting that most problems occurred early in the course of therapy. However, the cumulative rate of AEs with both agents was high. Anemia was a major problem, with 18% and 13.7% of telaprevir and boceprevir recipients, respectively, requiring blood transfusions. Notably, RBV dose reduction was underutilized because the efficacy of this strategy was not recognized when the CUPIC trial began. Efficacy data in this study also were disappointing. In the Phase III trials of both agents, relapsers with cirrhosis had very high rates of SVR; however, in this real-world experience, despite high ontreatment viral suppression, overall SVR rates were low. Overall, the CUPIC data clearly demonstrate that triple therapy with an HCV PI is associated with a high risk for potentially severe toxicity and has somewhat

limited efficacy in patients with cirrhosis. Given the extremely promising data with other IFN-free and IFN-containing regimens that will soon be available, the CUPIC data should give us pause for thought before rushing to treat all patients with HCV PIs. ■ Dr. Feld has served as a consultant or advisory board member for AbbVie, Achillion, Boehringer Ingelheim, Gilead Sciences,

H E PAT O L O G Y I N F O C U S

25

‘The findings highlight the importance of conducting real-world studies to evaluate the true effectiveness and safety of approved regimens when their use expands beyond the highly selected trial populations.’ —Jordan Feld, MD, MPH

Janssen Pharmaceuticals, Merck & Co., Roche and Vertex Pharmaceuticals. He has received grant support from Boehringer

Ingelheim, Gilead Sciences, Roche and Vertex Pharmaceuticals. see Top Liver, page 26


26

H E PAT O L O G Y I N F O C U S

Top Liver continued from page 25

Jacqueline O’Leary, MD, MPH Medical Director Inpatient Liver and Transplant Unit Baylor University Medical Center Dallas, Texas

S

afety and Efficacy of Interferon-Free Regimens of ABT-450/R, ABT-267, ABT-333 ± Ribavirin in Patients With Chronic HCV GT1 Infection: Results From The AVIATOR Study (Kowdley KV et al. EASL Abstract 3) This subanalysis of the AVIATOR study included 247 non-cirrhotic patients with HCV GT1 who received a fourdrug treatment regimen for 12 or 24 weeks in a randomized open-label fashion. Treatment included 100 or 150 mg once daily of ABT-450, a potent HCV NS3/4A PI, administered orally with 100 mg of ritonavir, as well as 25 mg once daily of ABT-267, an HCV NS5A inhibitor, 400 mg twice daily of ABT333, a non-nucleoside HCV polymerase inhibitor, and 1,000 to 1,200 mg daily of RBV, administered in two doses. The 12-week treatment group included 79 treatment-naive patients and 45 prior null responders; the 24-week group had 80 treatment-naive patients and 43 prior null responders. Findings showed that 99% of treatment-naive patients and 93% of null responders in the 12-week treatment arm achieved SVR at week 12, and 96% and 93% of the two groups, respectively, achieved SVR at week 24. In the 24-week treatment group, SVR at week 12 occurred in 93% and 98% of treatment-naive patients and null responders, respectively, whereas 90% and 95%, respectively, had SVR at week 24. One treatment-naive patient in the 12-week treatment group and two in the 24-week group experienced relapse. Additionally, three prior null responders in the 12-week group and one in the 24-week group experienced viral breakthrough. Six patients discontinued treatment due to AEs, but researchers considered only four of these related to treatment. Four serious AEs were reported, but only one—a case of arthralgia—was believed to be treatment-related.

Dr. O’Leary: This exciting 12-week all-oral HCV treatment regimen promises excellent SVR rates for patients without cirrhosis, even if they were prior null responders to PEG-IFN and RBV. Notably, characteristics previously identified as predictors of poor response—including HCV GT1a, high pre-treatment HCV viral load, IL28B genetic polymorphism and fibrosis stage 2 to 3—did not change overall SVR rates, which were consistently 93% or higher for treatment-naive patients and prior null responders.

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2013

The safety profile of this regimen was excellent. There were very few serious AEs or treatment discontinuations secondary to serious AEs. Elevations in bilirubin and alanine transaminase were both rare (2.8% and 0.6%, respectively). Questions that remain are how this brief, well-tolerated, IFN-free drug combination will perform in patients with compensated and decompensated cirrhosis, patients with HIV co-infection, and liver transplant recipients, especially given the drug–drug interactions that will need

to be managed in some of these patients. Despite these questions, the regimen is safe and effective, and given the risk for progressive fibrosis, hepatocellular carcinoma, insulin resistance and other nonhepatic consequences of HCV infection, it should no longer be possible for the U.S. Preventive Services Task Force to do anything other than follow the Centers for Disease Control and Prevention in recommending HCV screening for all baby boomers, followed by treatment of all persons identified with HCV infection.


GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST AUGUST 2013 2013

S

ustained Virologic Response With Daclatasvir Plus Sofosbuvir ± Ribavirin (RBV) in Chronic HCV Genotype (GT) 1–Infected Patients Who Previously Failed Telaprevir (TVR) or Boceprevir (BOC) (Sulkowski MS et al. EASL Abstract 1417) Researchers randomized 41 HCV GT1 patients without cirrhosis who had failed prior treatment with telaprevir or boceprevir in combination with PEGIFN and RBV to one of two treatment

regimens: 21 patients received 60 mg daily of daclatasvir, an HCV NS5A replication complex inhibitor, along with sofosbuvir 400 mg daily, and 20 patients received the same regimen plus RBV, both for 24 weeks. Most patients had received telaprevir previously, most were white and approximately 60% were men. Most patients had HCV GT1a and IL28B B genotype CT T or TT. T More than 80% of patients had METAVIR scores of F2 or higher. Mean HCV RNA for both groups was 6.3 log10 IU/mL. None

H E PAT O L O G Y I N F O C U S

of the participants had discontinued prior treatment with telaprevir or boceprevir because of an AE. Findings showed that 91% and 80% of

27

the RBV-free and RBV-containing treatment groups, respectively, experienced virologic response two weeks after treatment initiation, and 100% had a virologic

‘This pivotal abstract delivered a once-daily, all-oral HCV treatment regimen, with minimal side effects or drug–drug interactions.’ —Jacqueline O’Leary, MD, MPH

response by the end of treatment. All participants also experienced SVR at weeks 4 and 12. Common mild or moderate AEs in both groups included fatigue, headache, alopecia and arthralgia. Constipation and diarrhea each occurred in 5% of nonRBV recipients and in 20% of RBV recipients. No severe AEs occurred in the RBV-free group. Dr. O’Leary: This pivotal abstract delivered a once-daily, all-oral HCV treatment regimen, with minimal side effects or drug–drug interactions. At week 12, 100% of patients who had failed first-generation HCV PI treatment achieved SVR. We all have seen multiple exciting combinations with and without IFN that exceed currently available HCV treatment regimens and produce higher SVR rates, shorter courses of therapy and dramatically fewer side effects. Although a small study, this trial is the first to promise not just an IFN- and RBV-free regimen, but a cure for true telapreviror boceprevir-related treatment failures. Sulkowski et al have raised the bar on what is required for a successful HCV regimen to an all-time high!

N

atural History of Inflammatory Bowel Disease After Liver Transplantation for Primary Sclerosing Cholangitis (Singh S et al. DDW Abstract 40) Researchers from Mayo Clinic examined data from 101 patients with primary sclerosing cholangitis (PSC) who underwent liver transplantation for non-cholangiocarcinoma indications between 1998 and 2008 and who were followed for a median of 8.4 years post-transplantation. Eighty of these patients had inflammatory bowel disease (IBD) before liver transplantation. The researchers limited their analysis to 55 patients with IBD who had an intact colon at the time of transplantation. Pre-transplantation, 58% of patients (32 of 55) were not receiving medications see Top Liver, page 28


28

H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2013

New Guidelines for Liver Transplant Anesthesia a ‘Landmark’ BY DAVID WILD Experts are applauding new recommendations for the administration of anesthesia during liver transplant surgery that offer formal recognition that anesthesiologists are critical to optimizing transplant patient care. The document, from the Organ Procurement and Transplant Network (OPTN)/United Network for Organ Sharing (UNOS), set qualification requirements for directors of liver transplant anesthesia. “The recommendations are really a landmark development in that they urge closer cooperation and goodwill between the transplant and anesthesia communities and address the best interests of our patients,” said Susan Mandell, MD, PhD, professor of anesthesiology at the University of Colorado Health Sciences Center, in Aurora. The recommendations, passed as an OPTN/UNOS bylaw, call for transplant centers to appoint a director of liver transplant anesthesia (see http:// optn.transplant.hrsa.gov/policiesandby laws2/by laws/optnby laws/pdf s/ bylaw_162.pdf ). They also specify the educational and transplant experience that such directors should have in order to be appointed to the position, as well as their duties in the position (see sidebar, page 29). Although the recommendations are not binding, if OPTN/UNOS determines that lack of adherence to the guidelines contributes to poor outcomes at a center, it can recommend that the directorship guidelines be implemented. In addition, the Centers for Medicare & Medicaid Services has authority to

decertify programs if they have poor outcomes, especially if recommended guidelines were not followed, Dr. Mandell explained.

to the survey indicated they already had a director in place before the recommendations were issued. Although most centers did not have formal directorship

Table. Selected Survey Responses From Academic Liver Transplant Centers Survey Item

Response (N=42)

Centers with directors of anesthesia for liver transplantation

100%

Centers with written criteria describing the directorship position

38%

Directors who completed a fellowship in liver transplantation

0%

Centers requiring a specific number of liver transplant cases to qualify as director

4.3%

Centers requesting that directors have postgraduate liver transplant experience

82%

Directors at small, medium and large centers earning ≤5 CME credits annuallya

47%, 35% and 31%

Directors attending transplant patient selection committees

65%

Centers with anesthesiologist-developed liver transplant patient care protocol

80%

CME, continuing medical education a Center size defined by annual volume of liver transplants: small, 10-49; medium, 50-99; large, >100

really in their recognition of anesthesiologists as essential to achieving the best care possible for liver transplant patients,” Dr. Mandell said. “They support the emerging leadership in liver transplant anesthesia and bring greater uniformity to the directorship position.” The recommendations strengthen a multidisciplinary model of liver transplantation by calling for directors to be involved in all aspects of care: perioperative consults, transplant candidate selection, morbidity and mortality conferences, postoperative patient visits and development of intraoperative guidelines. Several studies have demonstrated that specialized liver transplant anesthesia teams can improve patient outcomes. For example, researchers at the University of Wisconsin showed that liver transplant anesthesiologists reduce the need for blood transfusions and shorten intensive care unit stays following liver transplantation (Hevesi ZG et al. Liver Transpl 2009;15:460-465). “This was one of the pieces of evidence that OPTN/UNOS considered in its deliberations about the role of anesthesiologists in the integrated care model,” Dr. Mandell said.

Fostering Partnerships While Dr. Mandell welcomed the new bylaw, she said it does not introduce new practices—a conclusion she arrived at after she and several of her co-investigators surveyed adult academic transplant centers and private programs and compared the recommendations with current practice (Mandell MS et al. Liver Transpll 2013;19:425-430). The 42 adult academic centers that responded

Top Liver continued from page 27

for IBD, 38% (21 of 55) were undergoing treatment with 5-aminosalicylic acid (5-ASA), one patient was on immunomodulators or corticosteroids, and one patient was taking a tumor necrosis factor (TNF) inhibitor. After transplantation, 51% of patients had stable disease, 47% required treatment initiation or intensification and one patient experienced improvement. Of the 32 patients who had not required medication before transplantation, after transplantation and despite transplant-related immunosuppression, six patients initiated use of 5-ASAs, nine started immunomodulators and/ or corticosteroids and one patient began treatment with an anti-TNF or required surgery; 16 patients did not require post-transplantation medication. Among the 21 patients who had been treated with 5-ASAs pretransplantation, after transplantation 11 patients remained

criteria, the majority of directors had the specialized liver transplant education and the experience in liver transplantation or a related high-acuity care specialty that the guidelines call for, Dr. Mandell said. Furthermore, most directors performed similar administrative duties to those specified in the OPTN/ UNOS bylaw (Table). “The importance of these guidelines is

on 5-ASAs, six patients required immunomodulators and/or corticosteroids and three patients required an anti-TNF or surgery. Thirteen patients required a colectomy during the follow-up period. Risk for disease progression after transplantation was 11% at one year, 36% at five years and 45% at 10 years, with use of tacrolimus increasing the risk (hazard ratio [HR], 5.6; 95% confidence interval, 1.1-103.4). Recurrence of PSC was associated with a decreased risk for disease progression (HR, 0.2; 95% CI, 0.1-0.6). Finally, among the 21 patients who did not have IBD before liver transplantation, 11 developed the disease during follow-up. The risk for developing de novo IBD at one, five and 10 years after transplantation was 4.8%, 38.1% and 47.6%, respectively. The researchers did not identify any risk factors for de novo post-transplantation development of IBD. Dr. O’Leary: These findings are surprising: A

David J. Reich, MD, professor and chief of the Division of Multiorgan Transplantation and Hepatobiliary Surgery, at Drexel University College of Medicine and Hahnemann University Hospital, in Philadelphia, co-authored the survey study with Dr. Mandell and her colleagues. He said the guidelines “should improve liver transplant anesthesia support and partnership between transplant and anesthesia teams.”

disease that is believed to be immune-mediated has a high risk for progression and de novo development in liver transplant recipients, despite their use of posttransplantation immunosuppressive therapy. Most of the 80 patients who had IBD before transplantation had mild disease, and despite post-transplantation immunosuppression, nearly half of the patients required initiation or escalation of therapy for IBD after transplantation. Furthermore, 47.6% of patients without IBD before transplantation developed de novo IBD after transplantation. Additionally, there was a 21.3% 10-year risk for colectomy after transplantation. Hopefully, this information will lead to greater insight into the mechanisms of IBD disease development and progression. ■ Dr. O’Leary has received fees for research, consulting or speaking from Genentech, Gilead Sciences and Vertex Pharmaceuticals.


H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2013

OPTN/UNOS Recommendations for Directors of Liver Transplant Anesthesia •

The director should have fellowship training in critical care medicine, cardiac anesthesiology or liver transplant, including perioperative care of at least 10 liver transplant recipients or experience in the perioperative care of at least 20 liver transplant recipients within the past five years.

The director should earn a minimum of eight hours of credit in transplant-related educational activities within the three years preceding appointment.

BY DAVID WILD •

The director will be responsible for establishing internal policies for anesthesiology participation in perioperative transplant patient care.

The policy must establish a clear communication channel between the transplant anesthesiology service and other liver transplant disciplines.

“This can only bolster safety and highquality outcomes,” said Dr. Reich, a past member of UNOS’ Liver and Intestine Transplant Committee and immediate past chair of the Standards Committee of the American Society of Transplant Surgeons (ASTS). “In every discipline, clinical programs are stretched in terms of resources. Because these guidelines have been issued by a governing organization, they provide transplant anesthesiologists with a strong case to ask hospital leadership for adequate resources so that they can ensure they meet the recommendations.” Although the survey did not include low-volume and private liver transplant centers, if the reaction from Porter Adventist Hospital, in Denver, is an indication of the broader response from this subset of programs, the guidelines should not be onerous. “The OPTN/UNOS guidelines are reasonable and manageable,” said Alan Qualls, MBA, the hospital’s director of Oncology, Robotics, and Transplant Services. His private medical center recently restarted its program and performs 10 to 15 liver transplants annually. “If the director is trained at a major center with a liver program, the requirements should already be in practice. Our director of liver transplant anesthesia already actively participates in the selection committee and clears patients medically with the primary liver surgeon during the evaluation process.” The feedback Dr. Reich received to date has focused on requests for more continuing medical education (CME) opportunities so that directors can meet the CME requirement stipulated in the guidelines. “The ILTS [International Liver Transplantation Society] has a one-day program for transplant anesthesiologists and the ASTS is increasing educational offerings to anesthesiologists,” he added. “We welcome collaboration with anesthesiologists and are trying to advertise educational opportunities, such as at the American Transplant Congress,” he said. ■

you’ve

met Mr. I’D-RATHER-KEEPMY- INDEPENDENCETHAN-KEEP-MY-NEXTDOCTOR’S-APPOINTMENT.

NOW his UC meet THERAPY GIAZO IS THE ONLY BID 5-ASA APPROVED TO INDUCE REMISSION IN MEN WITH MILD TO MODERATE ACTIVE ULCERATIVE COLITIS.1 INDICATION

PROVEN EFFICACY 57% of male patients on GIAZO achieved clinical improvement compared to 20% on placebo1

GIAZO® (balsalazide disodium) is indicated for the treatment of mildly to moderately active ulcerative colitis in male patients 18 years of age and older. Safety and effectiveness of GIAZO beyond 8 weeks have not been established.

CONTRAINDICATION GIAZO® (balsalazide disodium) tablets are contraindicated in patients with hypersensitivity to salicylates, aminosalicylates, or their metabolites or to any of the components of GIAZO tablets. Reference: 1. GIAZO Prescribing Information, 2012. Salix Pharmaceuticals, Inc.

Please see Brief Summary of complete Prescribing Information, including Important Safety Information on the opposite page. Please see complete Prescribing Information available at giazo.com. GIAZO® is a registered trademark of Salix Pharmaceuticals, Inc. ©2013 Salix Pharmaceuticals, Inc. All rights reserved. BZ 13/49

Learn more at giazo.com

29


DDW 2013

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Pancreatitis continued from page 1

“The addition of celecoxib [Celebrex, Pfizer] to octreotide may reduce the development of [SAP], especially by reducing the occurrence of organ failure and local complications,” said lead investigator Rui Wang, MD, PhD, of West China Hospital, Sichuan University in Chengdu. The combination is better at preventing SAP in patients who are predicted to worsen than in effectively treating SAP

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2013

once it occurs, the researchers found. “This indicates the necessity of early intervention,” Dr. Wang noted.

Rationale and Study Design Systemic inflammation contributes to the pathogenesis of SAP. Levels of somatostatin, an endogenous anti-inflammatory peptide, decline dramatically during the onset of SAP. Octreotide (Sandostatin, Novartis), a somatostatin analog, can raise circulatory somatostatin levels when given in continuous high doses and decrease

The following is a brief summary; please see complete Prescribing Information at www.Giazo.com. INDICATIONS AND USAGE GIAZO is indicated for the treatment of mildly to moderately active ulcerative colitis in male patients 18 years of age and older. Limitations of Use: • Effectiveness of GIAZO in the treatment of female patients was not demonstrated in clinical trials. • Safety and effectiveness of GIAZO therapy beyond 8 weeks have not been established. DOSAGE AND ADMINISTRATION The recommended dose for induction of remission of ulcerative colitis in adult male patients is three 1.1 g GIAZO tablets to be taken 2 times a day with or without food (6.6g per day) for up to 8 weeks. CONTRAINDICATIONS GIAZO is contraindicated in patients with hypersensitivity to salicylates or aminosalicylates, or their metabolites or to any of the components of GIAZO tablets. WARNINGS AND PRECAUTIONS Exacerbations of Ulcerative Colitis Balsalazide is converted to mesalamine, which has been associated with an acute intolerance syndrome that may be difficult to distinguish from an exacerbation of ulcerative colitis. In controlled clinical trials with GIAZO in adults with ulcerative colitis, 7% of male patients reported exacerbation of the symptoms of ulcerative colitis. Symptoms include cramping, acute abdominal pain and bloody diarrhea, sometimes fever, headache, and rash. Observe patients closely for worsening of these symptoms while on treatment. If acute intolerance syndrome is suspected, promptly discontinue treatment with GIAZO. Renal Impairment Renal impairment, including minimal change nephropathy, acute and chronic interstitial nephritis and renal failure, has been reported in patients given products that release mesalamine in the gastrointestinal tract. Evaluate renal function prior to initiation of GIAZO therapy and periodically while on therapy. Exercise caution when using GIAZO in patients with known renal dysfunction or a history of renal disease. Hepatic Impairment There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered mesalamine. Because balsalazide is converted to mesalamine, use caution and consider liver function testing when administering GIAZO to patients with liver disease. ADVERSE REACTIONS GIAZO was evaluated in one placebo-controlled trial (168 treated with GIAZO), one active-controlled trial (210 treated with GIAZO); and a subset of these patients also participated in an uncontrolled, open-label, extension study (additional 187 treated with GIAZO). The population consisted of patients with ulcerative colitis; the mean age was 43.1 years, 49% were male, and 84% were white. In a placebo-controlled clinical trial, the most common treatment-related adverse events occurring in at least 2% of male patients taking 6.6 g/day of GIAZO and at a rate greater than placebo, were anemia, diarrhea, pharyngolaryngeal pain, urinary tract infection, arthralgia, insomnia and musculoskeletal pain. 10% of patients in the GIAZO group and 13% of patients in the placebo group discontinued treatment due to an adverse reaction. The majority of adverse reactions were mild to moderate in severity. The most common serious adverse reactions in both the placebo and GIAZO groups were gastrointestinal disorders, which were mainly associated with symptoms of ulcerative colitis. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B. Reproduction studies were performed in rats and rabbits at oral doses up to 2 g/kg/day, 2.5 and 4.9 times the recommended human dose based on body surface area for the rat and rabbit, respectively, and revealed no evidence of impaired fertility or harm to the fetus due to balsalazide disodium. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

levels of inflammatory markers, thus attenuating immune-mediated inflammation. Dr. Wang’s team predicted that combining octreotide and another anti-inflammatory drug a different mechanism of action might have an even greater effect on inflammation associated with SAP. To this end, they tested celecoxib, a selective inhibitor of cyclooxygenase-2 (COX-2), which has been implicated as a crucial mediator of inflammation in SAP. The investigators assessed the combination therapy in a prospective

Mesalamine, a metabolite of GIAZO, is known to cross the placental barrier.

‘The addition of celecoxib

Nursing Mothers It is not known whether balsalazide disodium or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GIAZO is administered to a nursing woman.

to octreotide may reduce

Pediatric Use Safety and effectiveness of GIAZO tablets in pediatric patients have not been established. Geriatric Use Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a higher incidence of blood dyscrasias, i.e., neutropenia and pancytopenia in patients who were 65 years or older who were taking mesalamine-containing products. GIAZO is converted into mesalamine in the colon. Caution should be taken to closely monitor blood cell counts during therapy. Clinical trials of GIAZO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing GIAZO. CLINICAL STUDIES A double-blind, placebo-controlled, multi-center trial was conducted in 250 adult patients with mildly to moderately active ulcerative colitis. Disease activity was assessed using a modified Mayo Disease Activity Index1 (MMDAI), which was a sum of four subscores (bowel frequency, rectal bleeding, endoscopic appearance, and physician’s global assessment), each ranging from 0 to 3, with higher scores indicating worse disease. The median baseline MMDAI score was 8 and the median baseline rectal bleeding subscore was 2. Patients were randomized 2:1 to receive 8 weeks of treatment with either GIAZO 3.3 g twice daily or placebo. After 8 weeks of treatment, the proportion of patients who met the definition of Clinical Improvement was greater for the GIAZO-treated group (55%) compared to the placebo group (40%) (P=0.0237). These differences were statistically significant in the overall population; however, these effects were entirely driven by the results in the male subpopulation (57% with GIAZO vs. 20% for placebo). Effectiveness of GIAZO was not demonstrated in the female subpopulation in the clinical trial (54% with GIAZO vs. 58% for placebo). POST MARKETING EXPERIENCE These adverse reactions have been chosen for inclusion due to a combination of seriousness, frequency of reporting, or potential causal connection to products which contain or are metabolized to mesalamine, including balsalazide. Cardiovascular and Vascular: myocarditis, pericarditis, vasculitis Respiratory: alveolitis, pleural effusion, pneumonia (with and without eosinophilia) Gastrointestinal: pancreatitis Renal: interstitial nephritis, renal failure. Hepatobiliary Disorders: elevated liver enzymes (AST, ALT, GGT, LDH, alkaline phosphatase), elevated bilirubin, jaundice, cholestatic jaundice, cirrhosis, hepatocellular damage including liver necrosis and liver failure, Kawasaki-like syndrome including hepatic dysfunction. Some of these cases were fatal. Dermatological: alopecia, pruritus HOW SUPPLIED GIAZO is available as oval, yellow, film-coated tablets containing 1.1 g balsalazide disodium, with BZT debossed on one side of the tablet. NDC 65649-102-02 Bottles of 180 tablets STORAGE AND HANDLING Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). See USP Controlled Room Temperature. Reference: 1. Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mild to moderately active ulcerative colitis: a randomized study. N Engl J Med. 1987;317:1625-9.

Salix Pharmaceuticals, Inc. Raleigh, NC 27615

BZ 12/02

randomized controlled trial of 183 patients who were admitted to the hospital within 48 hours of the onset of symptoms of SAP. Patients with Acute Physiology and Chronic Health Evaluation II (APACHE II) scores of 8 or greater and multiple organ failure (MOF) scores of 2 or greater, were characterized as having “confirmed” SAP, and those with APACHE II scores of 8 or greater but MOF scores of less than 2, were classified as “predicted” SAP. Each of the two groups of patients with “confirmed” or “predicted” SAP were randomized into two treatment arms: octreotide alone (50 mcg per hour for three days, plus 25 mcg per hour for four days) or octreotide (same schedule) plus celecoxib (200 mg twice daily for seven days). A healthy control group (n=64) was included for comparison of somatostatin and inflammatory markers.

the development of severe acute pancreatitis, especially by reducing the occurrence of organ failure and local complications.’ —Rui Wang, MD, PhD

The primary outcomes of the study were the incidence of patients who evolved from predicted SAP to actual SAP and the percentage of patients who experienced amelioration of SAP. Secondary outcomes were complications, APACHE II scores, and plasma levels of somatostatin, tumor necrosis factor (TNF)–α interleukin (IL)-6 and IL-10.

Prevention of Worsening SAP The researchers found that the addition of celecoxib to octreotide proved to be protective against the development of SAP but did not alleviate SAP that was documented at baseline. After treatment of high-risk patients, the incidence of SAP was approximately 37% with octreotide alone compared with 15% in the combination therapy group, for a 70% reduction in risk (P=0.001). P “This indicated that celecoxib efficiently prevents the occurrence of SAP, and when you look at the details, you see that it is mostly by preventing organ failure and local complications,” Dr. Wang noted (Table). In the “predicted” SAP group,


DDW 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2013

Table. Outcomes in Patients With Severe Acute Pancreatitis Treated With Octreotide and Celecoxib Outcome

Octreotide Alone (n=90)

Octreotide–Celecoxib Combination (n=93)

P Value

Organ failure at day 8

25.6%

12.9%

0.030

CTSI score ≥6 at day 8

36.7%

15.1%

0.001

Local complications at one month

36.7%

15.1%

0.001

APACHE II score at day 8 (median)

5.3

3.8

0.017

Length of hospital stay, days (mean)

13.33

10.74

0.033

He said he might consider this combination for patients he suspects will develop SAP, such as those with a dilated common bile duct and/or abnormal liver function tests suggestive of choledocholithiasis, but no clinical pancreatitis. “This might be a patient you could start this [treatment] on, based on the evidence in this study, as opposed to treating once the horse is out of the barn and it’s too late to help.” ■ Drs. Wang and Katzka reported no relevant conflicts of interest.

C S , co CTSI, computed pu p ed tomography o og g ap p y se severity e y index de

celecoxib significantly reduced systemic and metabolic complications at day 8, including the occurrence of pulmonary failure, acute respiratory distress syndrome, renal failure and encephalopathy, as well as pseudocyst and abscess at one month. “But when it comes to patients with actual SAP, the results are not that promising,” Dr. Wang said. No differences were seen in the “confirmed” SAP group in the occurrence of organ failure, local complications, computed tomography severity index scores, MOF scores or hospital stay. In patients with confirmed SAP at study entry, nearly 80% of patients in each treatment arm had SAP at the study’s conclusion. The combination treatment including celecoxib did, however, significantly reduce the incidence of acute respiratory distress syndrome and encephalopathy at day 8 in this group. Both treatments enhanced the day 8 levels of somatostatin to levels of those seen in healthy controls. Only the octreotide plus celecoxib combination reduced levels of the pro-inflammatory markers IL-6 and TNF-α to that of healthy controls. The anti-inflammatory cytokine IL-10 was significantly elevated in both treatment groups, but levels were higher in the combination group. In conclusion, Dr. Wang noted that the benefit of this anti-inflammatory combination is more obvious in patients with predicted SAP, not actual SAP. “This is the first randomized controlled trial that combines octreotide and celecoxib. We see a suppression of the extensive inflammation of this dynamic process, and this may prevent the most severe form of this disease—even death from it,” Dr. Wang said.

Possible Prophylaxis David A. Katzka, MD, of Mayo Clinic, Rochester, Minn., who moderated the abstracts session, called this “a very good study” whose findings are applicable to the prophylaxis of pancreatitis, although not so much for treating established disease.

31

P

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Held in con njuncttion with the American College of Gastroentterolog gy 78th Annual Scientific Meeting Friday, October 11, 2013 San Diego Convention Center San Diego, California Join the Amerrican Socciety for Gastrointestinal Endoscopy in San Diego, CA for a ccourse that will focuss on the state-of-the-art endoscopic management of patients with gastroin ntestinal diseases, alon ng with new n technologies available to the Endoscopist. Through did dactic lecctures and video casses, world d-renowned experts will discuss topics including: · New techniiques forr performing colonoscopy, and large colonic polyp resection · Various ERC CP cannu ulation techniques and management of stones, strictures an nd bile duct d canccers · Manageme ent of Barrrett’s esophagus · Gastrointesstinal bleeding management techniques · Advanced imaging in the gastrointestinal tract · Cutting edg ge techniques for the management of early cancers and achalasia The ASGE Posstgraduatte Course takes place in conjunction with the American Co ollege of Gastroenterollogy Ann nual Scientific Meeting. Pre-registration deadline is Friday, SSeptemb ber 20, 20 013. To register, visit www w.acgmeetings.org.

Course Directors Ashley L. Faulx, MD, FASGE University Hospitals Case Medical Center Cleveland, OH Raj J. Shah, MD, FASGE University of Colorado Anschutz Medical Campus, Aurora, CO


32

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2013

Billion-Dollar Savings From Biosimilar Versions of Popular Brand-name Biologics Projected BY DAVID WILD ORLANDO, FLA.—National drug spending could be cut by $250 billion between 2014 and 2024 if only 11 biosimilar versions of current best-selling biologics are approved during those 10 years, Express Scripts has forecasted (www.

lab.express-scripts.com). The company’s vice president of research and analysis, Sharon Frazee, said the projection is based on an “uber-conservative” model and suggested the savings could even be higher. “There are 92 patent expiries coming up,” Ms. Frazee said. “We only included the 11 that we believe are certainly going

to have competitor biosimilars come to market.” The analysis, which was presented at the Express Scripts Outcomes Symposium, compared a scenario in which 11 generic versions of current best-selling biologics would be available between 2014 and 2024 with one in which only the branded biologics would

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be available (Table). In the biologicsonly scenario, spending on the 11 drugs was estimated to increase from $33.6 billion in 2014 to $121 billion in 2024. In contrast, if the FDA were to approve 11 biosimilars, savings in 2024 would be $81.3 billion, Express Scripts projected. The cumulative savings between 2014 and 2024 would be $250 billion if these 11 biosimilars were approved. Molly Burich, MSc, a market analyst not involved in the research, said the figure also could be lower than the analysis suggests. “This report assumes biosimilars will be discounted at 30% relative to their branded competitors, but the thinking over the past few years has led to an erosion of this number down to between 20% and 25%,” said Ms. Burich, who is assistant director of Reimbursement Strategy and Health Policy at Xcenda, an AmerisourceBergen Consulting Services company based in Charlotte, N.C.

Biosimilar Landscape Hazy One reason expectations have been curbed is that the FDA may create an onerous biosimilar approval

Table. Brand-name Biologi iologics That Could Be Replac ced By Biosimilars Brand Name Generic Name

Manufacturer

Avastin

Bevacizumab

Genentech

Epogen

Epoetin alfa

Amgen

Herceptin

Trastuzumab

Genentech

Humira

Adalimumab

AbbVie

Intron A

Interferon alfa-2a

Merck

Neulasta

Pegfilgrastim

Amgen

Neupogen

Filgrastim

Amgen

PegIntron

Peginterferon alfa-2b

Merck

Procrit

Epoetin alfa

Janssen

Remicade

Infliximab

Janssen Biotech

Rituxan

Rituximab

Genentech

Source: Express p Scripts Scr ripts p


33

GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ AUGUST 2013

FDA Plans for Biosimilar Approval Pathway BY DAVID WILD In a statement issued on May 22, a representative from the FDAâ&#x20AC;&#x2122;s Center for Drug Evaluation and Research said: â&#x20AC;&#x153;The type and amount of data and information that will be sufficient to demonstrate biosimilarity will be determined on a program-specific basis.â&#x20AC;? At press time, the spokesperson noted that the FDA was still reviewing public comments

pathway, Ms. Burich noted. As a result, manufacturers might be required to submit extensive preapproval data and to conduct postmarketing studies. Express Scripts did not take the costs of gathering these data into consideration when constructing its 30% discount rate, Ms. Frazee said. Instead, Express Scripts based the discount assumption on the historical costs of biosimilars, including those currently available in Europe. Other costs that could cut into any savings include those associated with distributing drugs and providing physician reimbursement assistance and patient support programs. â&#x20AC;&#x153;All of these elements will require a big investment on the part of biosimilar manufacturers and will have a significant see Biosimilars, page 34

Approval Date

Patent Expiration Date

2012 Sales

02/06/2004

06/18/2019

$2,662,842,000

06/01/1989

05/26/2015

$2,254,245,000

09/25/1998

08/27/2019

$1,837,693,000

12/31/2002

12/31/2016

$4,505,380,000

06/04/1986

08/26/2020

$94,009,000

01/31/2002

10/20/2015

$3,472,988,000

02/20/1991

11/10/2013

$1,007,172,000

01/19/2001

08/26/2020

$121,828,000

06/01/1989

05/26/2015

$1,127,024,000

08/24/1998

09/04/2018

$3,796,422,000

11/26/1997

07/05/2015

$3,183,625,000

on the subject and has yet to finalize three draft guidances. The administration still needs to decide how to develop future policies on biosimilars, the statement said, including guidance on what clinical pharmacology data they need from manufacturers to show biosimilarity to a reference product. â&#x20AC;&#x153;We will be able to provide meaningful advice on the scope and extent of necessary animal and human testing after a thorough review of

data from structural and functional analyses [for a given product],â&#x20AC;? the FDA statement said. â&#x20AC;&#x153;Additional animal and clinical studies should be designed to address residual uncertainty about the biosimilarity between the two products to ensure such testing is appropriately targeted.â&#x20AC;? Draft guidance on the development and approval of biosimilars can be found at www.fda. gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ Biosimilars/default.htm.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2013

Biosimilars continued from page 33

impact on the discounts they can offer,” she said. Both Ms. Burich and Ms. Frazee agreed that the extent to which a biosimilar will be used interchangeably with its branded competitor will mean the difference between small and large savings. Express Scripts assumed that 55% of the 11 biosimilars included in its model will be used interchangeably by payors and physicians by 2020,

primarily in patients newly prescribed a biologic treatment. However, the degree of interchangeability could be lower or higher, Ms. Burich said. “Interchangeability is a critical unknown and could have a huge impact on overall savings,” she noted. Ms. Burich added that payors likely will follow FDA policy. Based on preliminary guidance, she said, the administration likely will be conservative in granting

interchangeability—at least initially. However, “if biosimilar manufacturers can offer huge discounts, payors may go ahead and mandate that a biosimilar be used in new patients, at least.”

Physicians Protest High Cost of Biologics Hagop Kantarjian, MD, chairman of the Leukemia Department at the

University of Texas MD Anderson Cancer Center in Houston, and 120 other chronic myeloid leukemia (CML) experts published an article protesting the high cost of biologics (Experts in Chronic Myeloid Leukemia. Blood 2013;121:4439-4442). Dr. Kantarjian told Gastroenterology & Endoscopy News that the FDA needs to implement an accelerated approval process. “Of course safety concerns need to be addressed, but they also shouldn’t delay in getting biosimilars to market,” he said.

‘If there was any doubt in my mind that a biosimilar was not as effective as the

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However, Dr. Kantarjian’s colleague, Leonard Zwelli ling, MD, MBA, professor of medicine and pharmacology at MD Anderson, was more cautious about ut the idea. “In malignant disea eases, where the first pass is critical, you want wa to come at the disease with your bestt guns first,” said Dr. Zwelling, who alsoo has a research interest in health policy and economics. “If there was any doubt in my mind that a biosimilar was not as effective as the biologic, I would choose the branded drug.” Dr. Zwelling admitted that extensive clinical data requirements could discourage manufacturers from developing biosimilars altogether. In that case, he said, “the likelihood that big savings could result from biosimilars is about zero.” ■ Drs. Kantarjian and Zwelling and Ms. Burich reported no relevant conflicts of interest.


35

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2013

Biosimilars Face Many Hurdles in Approval Process BY GINA SHAW LAS VEGAS—“The biosimilars game is a long game, a very long game, indeed.” So wrote the editors of Nature Biotechnologyy in the magazine’s April 5 online edition. This assessment neatly sums up the view of what’s coming with biosimilars shared by experts at the 2013 Armada Summit conference. In other words, despite the fact that the FDA has drafted three guidances on a new approval pathway aimed at getting these follow-on biologics to market, it still could be several years before the first such product becomes available. The obstacles to getting a biosimilar to market are “huge,” said David Galardi, PharmD, co-founder of the health care consulting firm Apogenics, Inc., during a session on the topic at the conference, which targets stakeholders in specialty pharmacy. “Biologics, by definition, are hard to make,” he said. “I can’t just go buy a tablet press and pour powder in there and watch it pour off some machine.” Unlike traditional small-molecule generic drugs, such as the current oral generic drugs, biosimilar versions of large-molecule drugs (biologics) will require successful clinical trials to get FDA approval. “For the standard generic drug application, a 505(j) filing, there’s no trial required,” Dr. Galardi noted. “It’s effectively just a pharmacokinetics one-to-one analysis. But the filing for a biologic is a 301(k), which requires a full efficacy and safety workup, which means a clinical trial.” Developers of biologics will have a much bigger advantage over their imitators than is the case with smallmolecule generics, Dr. Galardi added. “The litigation process for biosimilars is substantial. Effectively, the ‘bio-sponsor’ must disclose to the innovator their application and their manufacturing process, providing a clear advantage to the innovator company. [The innovator company] also likely will have a lower cost of production and deep roots in the supply chain for raw materials. Innovators are smart. Expect them to become aggressive in defending their turf.” Another obstacle for biosimilars is that providers initially may be reluctant to switch to these products, more so than is the case with small-molecule generics. “Vigilance to immunogenicity and related adverse events is an important safety concern with biologics,”

Dr. Galardi noted. “Say you’ve had Mary on a particular drug and she’s tolerant, and somebody else comes along and says, ‘try another drug that looks similar.’ Mary goes to the infusion center and codes. Think that’s possible? Absolutely. It happens.” When biosimilars finally do come to market, they most likely will be covered under the medical benefit. Biosimilars are almost certain to upset the current cost structure of specific biologics.

“Supply and demand curves will shift,” Dr. Galardi predicted. “Unlike small-molecule generics, they will face a more complex pricing environment.” There’s a lot of savings potential from biosimilars, but it won’t be the same kind of numbers that were realized with generics because biosimilars are not as closely related to the innovator drug as traditional generics are to their branded counterparts, according to Mike Ellis, Walgreens’ corporate vice president for specialty

pharmacy and infusion. “There’s a reason they’re called biosimilars and not bioexacts,” he said. “These aren’t generic substitutes,” agreed Helen Sherman, PharmD, vice president of clinical pharmacy consulting at Solid Benefit Guidance. “They will be a brand,” she said. “But, in any case, despite all the press about biosimilars, I haven’t heard of one solid example indicating that there is a biosimilar coming out anytime soon,” Dr. Sherman said. ■

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F D A U P D AT E & P R O D U C T N E W S

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2013

Label Changes for Antihypertensive Drug Olmesartan To Include Sprue-like Enteropathy On July 3, the FDA warned that the blood pressure drug olmesartan medoxomil (marketed as Benicar, Benicar HCT, Azor and Tribenzor by Daiichi-Sankyo, Inc.), and its generic formulations can cause intestinal problems known as sprue-like enteropathy. Symptoms include severe, chronic diarrhea with substantial weight loss. Olmesartan medoxomil is an angiotensin II receptor blocker (ARB) approved for the treatment of high blood pressure, alone or with other antihypertensive agents, and is one of eight marketed ARB drugs. The FDA approved changes to the labels of olmesartan-containing drugs warning of the risk for symptoms of sprue-like enteropathy. ARB drugs other than olmesartan have not been associated with this finding. Reports of sprue-like enteropathy associated with olmesartan had been increasing during the past year, with physicians presenting data on the topic at last year’s American College of Gastroenterology meeting and this year’s Digestive Disease Week meeting, among other reports (see “Commonly Prescribed Antihypertensive Drug Linked to Sprue-Like Enteropathy in Some Patients,” by Monica Smith. Gastroenterology & Endoscopy News 2013;64:18-19 and Rubio-Tapia A et al. Mayo Clin Proc 2012;87:732-738). The FDA recommends that health care professionals tell patients to contact them if they develop severe, chronic diarrhea with substantial weight loss while taking an olmesartan-containing product, even if it takes months or years for symptoms to develop. Patients should contact their health care professional right away if they take an olmesartan-containing

product and experience severe diarrhea that does not go away, or have significant weight loss. The FDA will continue to evaluate the safety of olmesartan-containing products. Health care professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program at (800) 332-1088 or www.fda.gov/medwatch/report.htm. —Based on a press release from the FDA

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On June 26, a recall of Merck & Co.’s Recombivax HB Adult Formulation (Hepatitis B Vaccine [Recombinant]) was initiated due to the potential for a crack to have occurred in certain vials of one affected lot. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., initiated the voluntary recall of the vaccine. Lot Number J001183 of Recombivax HB Adult Formulation is the only lot affected by the recall. This lot was distributed solely within the United States between March 12, 2013 and May 2, 2013. Recombivax HB Pediatric/Adolescent Formulation and Recombivax HB Dialysis Formulation are not affected by the recall. According to the FDA, if a vial was cracked, the integrity of the vial and the sterility of the product may be compromised. Patients who may have been vaccinated with product from this lot do not require revaccination, the agency said. The FDA is asking customers to inventory and quarantine all product from Lot J001183, and follow instructions from Merck for the product’s return. Problems with this or any other vaccine product can be reported to the Vaccine Adverse Event Reporting System (http://vaers.hhs.gov/index), Lot Number J001183 of a national vaccine safety surveillance Recombivax HB Adult program cosponsored by the Centers Formulation is the only lot affected by the recall. for Disease Control and Prevention Photo courtesy of Merck & Co. and the FDA. —Based on a press release from the FDA


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F D A U P D AT E & P R O D U C T N E W S

GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ AUGUST 2013

FDA Approves Updated Label for Otsukaâ&#x20AC;&#x2122;s H. pylorii Breath Test To Include Patients Taking PPIs Otsuka America Pharmaceutical Inc., recently announced k UBT for Helicobacter that their urea breath test, BreathTek pylorii Kit, may be administered to pa atients who are taking proton pump inhibitors (PPIs). Patients who have taken PPIs within two weeks can undergo the test, according to the updated BreathTek UBT Kit labeling information, but the test result needs to be interpreted with caution. If PPIs have been used within two weeks of breath testing and a positive breath test result is obtained, the result may be considered positive and managed d accordingly; est should be should a negative result occur, the te ation of PPIs. repeated two weeks after discontinua Otsuka still recommends that patientss should not have taken PPIs, antimicrobial medications or eks before bismuth preparations within two wee testing with the BreathTek UBT Kit. The label change is supported by published clinical studies that evaluated the effects of PPI use in patients taking this test. With this label update, patients on a PPI may be tessted using BreathTek UBT Kit earlier in the potential course of H. pylori infection, without discontinuing PPI use, resulting in an opportunity for earlier detection and initiation of eradication therapy for H. pylorii infection. ection The company pointed out that due to its correlation with peptic

ulcers, many patients with H. pylorii infection take PPIs to reduce the amount of acid produced by the stomach. BreathTek UBT T Kit is a noninvasive test that measure es the ratio of 13CO2 to 12CO2 in patientsâ&#x20AC;&#x2122; breath samples to detect the pressence of urease associated with H. pyylorii infection, as well as to confirm tha at H. pylorii infection has been eradic cated after antibiotic therapy. Administered in four steps, the Breath hTek UBT Kit provides a conv venient alternative to difficult or invasive tests for H.. pylorii that require blood or stool samples, or endosc copy, according to a press sttatement from Otsuka. BreathTe ek UBT Kit has demonstrated high sensitivity (95.5%) and specifficity (96%) in confirming the era adication of H. pylori following an ntibiotic treatment in adult patients. â&#x20AC;&#x201D;Based Base on a press release from Otsuka America Pharmaceutical Inc.

BreathTek UBT for Helicobacter pylori Kit Photo courtesy of Otsuka America Pharmaceutical Inc.

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John Vargo, MD, MPH

Donald Kirby, MD

Vice Chairman, Digestive Disease Institute Chairman, Gastroenterology and Hepatology

Director, Center for Human Nutrition

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NEW PRODUCT ANNOUNCEMENT

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2013

39

Fuse 330-Degree Colonoscope Receives FDA 510(k) Clearance During the 2013 Digestive Disease Week meeting, EndoChoice Inc., unveiled its new Fuse Full Spectrum Endoscopy (Fuse) system, which recently received FDA 510(k) clearance. According to EndoChoice, Fuse significantly improves the accuracy of colonoscopy and reduces the number of adenomas missed. The Fuse system comprises a proprietary arrangement of three small cameras at the tip of a flexible endoscope, allowing endoscopists to see nearly twice as much surface area as they can with traditional endoscopes that have only one camera, the company said. The Fuse system allows endoscopists to see tissue within and behind colonic folds, problem areas that can go undetected when using traditional colonoscopes, EndoChoice said. “Traditional endoscopes provide up to 170 degrees of forward vision,” said Ian M. Gralnek, MD, MSHS, associate professor of medicine/gastroenterology at the Rappaport Family Faculty of Medicine Technion-Israel Institute of Technology in Haifa, Israel. “The advantage of Fuse is that it allows endoscopists to examine twice the anatomy with a wide, 330-degree view,” said Dr. Gralnek, who was an investigator on a trial that compared Fuse with traditional, forward-viewing colonoscopy. In a multicenter trial conducted in the United States, Europe and Israel, Dr. Gralnek and his colleagues performed a series of tandem colonoscopies comparing traditional endoscopes and the new Fuse system. After the first inspection, each patient in the study immediately underwent a second colonoscopy performed by the same endoscopist using the competing endoscope. Data from 185 patients showed that 42% of adenomas were missed with traditional colonoscopes, whereas the Fuse system missed 8%. After 28 adenomas were found using traditional endoscopes, another 20 were found with the Fuse system, for an incremental find rate of 71%. (For more information, see “New Colonoscope Offers Sweeping, 330-Degree Views of the Colon; Fuse Generates ‘Huge’ Interest at DDW Meeting,” by Audrey Andrews. Gastroenterology & Endoscopy News July 2013;64:1,14.) EndoChoice plans to expand the use of Fuse beyond the current pilot sites to more centers around the world this year. “Since we announced the expansion of our company in January, our

teams in Israel, Germany and the United States have been working diligently to develop and launch the revolutionary Fuse endoscopy system,” said Mark Gilreath, founder and CEO of EndoChoice. For more information on the Fuse system, visit www.endochoice. com/fuse. —Based on a press release from EndoChoice Inc.

The Fuse system comprises a proprietary arrangement of three small cameras at the tip of a flexible endoscope, allowing endoscopists to see more surface area compared with traditional endoscopes. Photo courtesy of EndoChoice Inc.

MoviPrep®

USE IN SPECIFIC POPULATIONS

(PEG-3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate, and ascorbic acid for oral solution) The following is a brief summary only; see full Prescribing Information for complete product information.

Pregnancy: Pregnancy Category C. Animal reproduction studies have not been performed with MoviPrep. It is also not known if MoviPrep can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. MoviPrep should be given to a pregnant woman only if clearly needed.

INDICATIONS AND USAGE MoviPrep is an osmotic laxative indicated for cleansing of the colon as a preparation for colonoscopy in adults 18 years of age or older.

Nursing Mothers: Because many drugs are excreted in human milk, caution should be exercised when MoviPrep is administered to a nursing woman.

CONTRAINDICATIONS

Pediatric Use: MoviPrep is contraindicated in patients with the following conditions: gastrointestinal The safety and effectiveness of MoviPrep in pediatric patients has not been The Fuse system comprises a pro(GI) obstruction, bowel perforation, gastric retention, ileus, toxic colitis or toxic established. prietary of arrangement of three small megacolon, or hypersensitivity to any components MoviPrep. cameras at the tip of a flexible Geriatric endo- Use: WARNINGS AND PRECAUTIONS Of the 413 patients in clinical studies receiving MoviPrep, 91 (22%) patients were scope,medications allowing to see Use with caution in patients using concomitant thatendoscopists increase aged 65 or older, while 25 (6%) patients were over 75 years of age. No overall the risk of electrolyte abnormalities (such as diuretics, angiotensin differences in safety or effectiveness were observed between geriatric patients more surface areaconverting compared with enzyme (ACE)-inhibitors or angiotensin receptor blockers (ARBs), patients and younger patients, and other reported clinical experience has not identified traditional endoscopes. with known or suspected hyponatremia), patients at increased risk of cardiac differences in responses between geriatric patients and younger patients, but arrhythmias, patients with a history of seizures or at increased risk of seizures greater sensitivity of some older individuals cannot be ruled out. Photo courtesy of EndoChoice Inc. such as patients taking medications that lower the seizure threshold (e.g., OVERDOSAGE tricyclic antidepressants), patients withdrawing from alcohol or benzodiazepines, patients with impaired renal function or patients taking concomitant medicaThere have been no reported cases of overdose with MoviPrep. Purposeful tions that affect renal function (such as diuretics, ACE inhibitors, ARBs, or or gross accidental ingestion of more than the recommended dose of MoviPrep non-steroidal anti-inflammatory drugs), patients with severe ulcerative colitis or might be expected to lead to severe electrolyte disturbances, including hyponainflammatory bowel disease, patients with impaired gag reflex or patients prone tremia and/or hypokalemia, as well as dehydration and hypovolemia, with signs to regurgitation or aspiration, patients with glucose-6-phosphate dehydrogenase and symptoms of these disturbances. The patient who has taken an overdose (G-6-PD) deficiency. should be monitored carefully, and treated symptomatically for complications. Osmotic laxatives may produce colonic mucosal aphthous ulcerations and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Concurrent use of stimulant laxatives and MoviPrep may increase the risk and is not recommended. The potential for mucosal ulcerations resulting from the bowel preparation should be considered when interpreting colonoscopy findings in patients with known or suspected inflammatory bowel disease. If gastrointestinal obstruction or perforation is suspected, appropriate diagnostic studies should be performed to rule out these conditions before administering MoviPrep. If a patient experiences severe bloating, abdominal distension, or abdominal pain, administration should be slowed or temporarily discontinued until symptoms abate. Patients with electrolyte abnormalities should have them corrected before treatment with MoviPrep. Patients should be advised to hydrate adequately before, during, and after the use of MoviPrep. If a patient develops significant vomiting or signs of dehydration after taking MoviPrep post-colonoscopy lab tests (electrolytes, creatinine, and BUN) should be considered. Fluid and electrolyte disturbances can lead to serious adverse events including cardiac arrhythmias, seizures and renal impairment. MoviPrep contains phenylalanine (233 mg per treatment). ADVERSE REACTIONS

In clinical trials, the most common adverse reactions for split dosing regimen (incidence •5%) were malaise, nausea, abdominal pain, vomiting, and upper abdominal pain. The most common adverse reactions for evening only dosing regimen (incidence •5%) were abdominal distension, anal discomfort, thirst, nausea, abdominal pain, sleep disorder, rigors, hunger, malaise, vomiting, and dizziness. Isolated cases of urticaria, rhinorrhea, dermatitis, and anaphylactic reaction have been reported with PEG-based products and may represent allergic reactions. Published literature contains isolated reports of serious adverse events following the administration of PEG-based products in patients over 60 years of age. These adverse events included upper gastrointestinal bleeding from a MalloryWeis tear, esophageal perforation, asystole, and acute pulmonary edema after aspirating PEG-based preparation. In addition to adverse reactions reported from clinical trials, the following adverse events have been identified during post-approval use of MoviPrep: hypersensitivity reactions including anaphylaxis (some of which were severe, including shock), rash, urticaria, pruritis, lip, tongue and facial swelling, dyspnea, chest tightness and throat tightness. Fever, chills and dehydration. DRUG INTERACTIONS Use caution when prescribing MoviPrep for patients with conditions, or who are using medications that increase the risk for fluid and electrolyte disturbances or may increase the risk of adverse events of seizure, arrhythmias, and prolonged QT in the setting of fluid and electrolyte abnormalities. Consider additional patient evaluations as appropriate. Oral medication administered within 1 hour of the start of administration of MoviPrep may be flushed from the gastrointestinal tract and the medication may not be absorbed.

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY Long-term studies in animals to evaluate the carcinogenic potential have not been performed with MoviPrep. Studies to evaluate potential for impairment of fertility or mutagenic potential have not been performed with MoviPrep. STORAGE Store carton/container at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). When reconstituted, store upright and keep solution refrigerated. Use within 24 hours. PATIENT COUNSELING INFORMATION s Advise patients to read the Medication Guide included in the full prescribing information. s Advise patients who require a diet low in phenylalanine that MoviPrep contains phenylalanine. s Ask patients to inform you if they have trouble swallowing or are prone to regurgitation or aspiration. s Instruct patients that each pouch needs to be diluted in water before ingestion and that they need to drink additional clear liquid (e.g., water, clear soup, fruit juice without pulp, soft drinks, tea and/or coffee without milk) according to instructions. s Inform patients that oral medications may not be absorbed properly if they are taken within one hour of starting each dose of MoviPrep. s Tell patients not to take other laxatives while they are taking MoviPrep. s Tell patients that MoviPrep produces a watery stool (diarrhea) which cleanses the colon before colonoscopy. Advise patients receiving MoviPrep to adequately hydrate before, during, and after the use of MoviPrep. Patients may have clear soup and/or plain yogurt for dinner, finishing the evening meal at least one hour prior to the start of MoviPrep treatment. No solid food should be taken from the start of MoviPrep treatment until after the colonoscopy. s Tell patients that the first bowel movement may occur approximately 1 hour after the start of MoviPrep administration. Abdominal bloating and distention may occur before the first bowel movement. If severe abdominal discomfort or distention occurs, stop drinking MoviPrep temporarily or drink each portion at longer intervals until these symptoms diminish. If severe symptoms persist, notify your health provider.

Rx only

Manufactured by: Norgine B.V. Hogehilweg 7 1101 CA Amsterdam Zuidoost Netherlands For: Salix Pharmaceuticals, Inc. Raleigh, NC 27615 © 2012 Salix Pharmaceuticals Inc. Feb 12

Web site: www.salix.com E-mail: customer.service@salix.com 8510 Colonnade Center Drive Raleigh, NC 27615 Tel. 866-669-SLXP (7597) All rights reserved.


MoviPrep® #1 prescribed branded purgative in the United States1

Seeing is believing MoviPrep has proven 89% excellent or good cleansing when used as a split dose2 ° Low-volume PEG-3350 provides consistent, clear visibility of the entire colon ° FDA approved for PM|AM Split Dosing™ ° Osmotic laxative with electrolytes ° Most common adverse reactions for split dosing (incidence ⱖ5%) are malaise, nausea, abdominal pain, vomiting, and upper abdominal pain. The most common adverse reactions for evening only dosing (incidence ⱖ5%) are abdominal distension, anal discomfort, thirst, nausea, abdominal pain, sleep disorder, rigors, hunger, malaise, vomiting, and dizziness.

Please see Brief Summary of complete Prescribing Information for MoviPrep on reverse. References: 1. Medi-Span® Price Rx® [database online]. Indianapolis, IN: Wolters Kluwer Health. http://www.medispan.com/drug-pricing-analysis-pricerx.aspx. Accessed July 13, 2012. 2. MoviPrep [prescribing information]. Raleigh, NC: Salix Pharmaceuticals, Inc.; 2012. Web site: www.salix.com 8510 Colonnade Center Drive, Raleigh, NC 27615 Tel·866.669.SLXP (7597) MoviPrep® is a registered trademark and PM | AM Split Dosing™ is a trademark of Salix Pharmaceuticals, Inc. © 2013 Salix Pharmaceuticals, Inc. All rights reserved. MOV11/41-4

www.MoviPrep.com


PRINTER-FRIENDLY VERSION AVAILABLE AT GASTROENDONEWS.COM

Diagnostic Tests for Helicobacter pylori

SOWJANYA KANNA, MD CARLA MARADEY-ROMERO, MD RONNIE FASS, MD Department of Medicine Division of Gastroenterology and Hepatology, Esophageal and Swallowing Center MetroHealth Medical Center Case Western Reserve University Cleveland, Ohio

A

bacterial pathogen found primarily in the stomach, Helicobacter pylori plays a pivotal role in the development of several gastrointestinal conditions, including gastritis, gastric mucosa-

associated lymphoid tissue (MALT) lymphoma, and peptic ulcer disease (PUD). There are many different tests available to detect active H. pylori infection; however, there is no defined role for routine screening. Diagnostic tests comprise invasive and noninvasive methods. The invasive tests include histology, rapid urease test (RUT), culture, and endoscopic urea breath test (E-UBT). Noninvasive tests include serology, urea breath test (UBT), and stool antigen test (SAT). Additionally, there are several molecular methods for detecting H. pylori, including polymerase chain reaction (PCR), real-time PCR, stool PCR, multiplex PCR, and fluorescence in situ hybridization (FISH). Determining which test to use to identify H. pylori infection depends on the specific clinical scenario.

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

Introduction H. pylori is a bacterial pathogen found primarily in the stomach. The organism has a significant role in the pathogenesis of gastritis, MALT lymphoma, and PUD.1 Chronic infection with H. pylori is endemic, affecting about half of the world’s population, especially those living in developing countries. The prevalence of H. pylori is closely linked to socioeconomic status. Economic development and the widespread use of antibiotics are likely responsible for the decline in prevalence of H. pylori.2 H. pylori is a gram-negative bacterium that favors the non–acid-secreting antral region of the stomach.

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS • AU G U ST 2 0 1 3

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Chronic inflammation of the antrum in the presence of H. pylori leads to suppression of the somatostatinsecreting antral D cells, which in turn results in excessive production of gastrin. Increased levels of gastrin lead to higher levels of acid secretion, putting patients with H. pylori infection at risk for gastric and duodenal ulcers. The carcinogenic potential of H. pylori is notable. The World Health Organization classifies H. pylori as a class I carcinogen.3 It is estimated that 75% of noncardia gastric cancers that occur worldwide can be attributed to H. pylori.4 The organism can lead to intestinal-type gastric adenocarcinoma through the atrophy–metaplasia– dysplasia–carcinoma sequence of progression (Figure). The distribution of H. pylori in the stomach of the host determines the clinical pathology associated with infection.5 Patients with antral-predominant gastritis are more likely to develop duodenal ulcer, whereas patients with corpus-predominant gastritis are more likely to present with gastric ulcer, gastric atrophy, intestinal metaplasia, and ultimately gastric adenocarcinoma.1 H. pylori is a factor in the development of MALT lymphoma, which has shown localized regression after H. pylori eradication.6

Indications for Testing There are several diagnostic tests available to identify H. pylori infection, but none is considered a gold standard. The disparity between the prevalence and clinical pathology of H. pylori negates any role for routine screening. Table 1 depicts the indications for H. pylori testing as recommended by the Maastricht IV consensus meeting and the American College of Gastroenterology guidelines.7,8

Superficial gastritis (H. pylori colonization)

ª Gastric atrophy

ª Gastric intestinal metaplasia

ª Gastric dysplasia

ª Gastric adenocarcinoma

Figure. Progression of Helicobacter pylori–induced gastritis to intestinal type gastric adenocarcinoma.59

2

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

Table 1. Established Indications For Helicobacter pylori Testing and Treatment7,8 Active peptic ulcer disease Past history of documented, untreated peptic ulcer disease Gastric mucosa-associated lymphoid tissue lymphoma After endoscopic resection of early gastric cancer Uninvestigated dyspepsia (in high pretest probability)

The Maastricht IV consensus report was developed by experts in 3 areas of H. pylori infection: indications, diagnostic testing, and treatment and prevention of gastric cancer.7 In addition to the recognized indications for H. pylori testing and eradication, the Maastricht III consensus report included gastric cancer in a first-degree relative, atrophic gastritis, unexplained iron deficiency anemia (IDA), and chronic idiopathic thrombocytopenic purpura (ITP). The Maastricht IV consensus meeting added several other indications, including a history of PUD prior to use of nonsteroidal anti-inflammatory drugs (NSAIDs), the presence of gastroduodenal ulcer in patients taking aspirin, and unexplained vitamin B12 deficiency.7 Table 2 outlines the sensitivities, specificities, advantages, and disadvantages of the different diagnostic tests for H. pylori infection.

Diagnostic Tests Routine screening for H. pylori infection is not performed in clinical practice. Testing is performed in patients who meet the aforementioned criteria. Currently available diagnostic tests fall into 2 main categories: invasive and noninvasive testing.

INVASIVE TESTS Histology Histologic testing is one of the most useful diagnostic tests for H. pylori infection and is considered by some the gold standard.9 The accuracy of the test depends largely on the site, size, and number of biopsy specimens. The ability of H. pylori to migrate and adapt to biochemical changes in the stomach, especially in the presence of medications that affect the gastric milieu, makes it essential that tissue samples


Table 2. Diagnostic Tests for Helicobacter pylori Infection7,8,60 Diagnostic Testsa

Sensitivity, Specificity, % % Clinical Use

Advantages

Disadvantages

Direct visualization of H. pylori, or indirect diagnosis of H. pylori via observation of inflammatory markers

Accurate

Expensive

Highly sensitive, specific

Requires trained personnel

Endoscopic tests Histology

95

99

Rapid urease 90 test

93

Diagnosis during endoscopy

Rapid results

Low sensitivity in the post-treatment setting

Culture

100

Determination of microbial sensitivities

Highly specific

Expensive

Determination of microbial sensitivities

Accurate

Not widely available or standardized

58.1

PCR

Used in research

Not widely available

Highly sensitive, specific

Non-endoscopic tests Urea breath test

≥95

≥95

Identification of active H. pylori infection Follow-up after eradication therapy

Stool 96 antigen test (monoclonal)

Serology

76-84

97

Identification of active H. pylori infection Follow-up after eradication therapy

79-90

High positive and negative predictive value, regardless of pretest probability

Sensitivity is affected by recent use of PPIs or antibiotics

High positive and negative predictive value, regardless of pretest probability

Sensitivity is affected by recent use of PPIs or antibiotics

Useful in patients with Widely available upper gastrointestinal High negative bleeding, those on predictive value chronic PPI therapy or other antireflux treatments, and those recently treated with antibiotics

Limited availability

Only monoclonal testing has similar accuracy as urea breath test Unsuitable for H. pylori assessment after eradication attempt

PCR, polymerase chain reaction; PPI, proton pump inhibitor a

The sensitivity of all endoscopic and non-endoscopic tests that identify active H. pylori infection is reduced by the recent use of PPIs, bismuth, or antibiotics.

be carefully obtained. In response to long-term use of antireflux medications, there is proximal migration of H. pylori in the stomach, resulting in a redistribution of gastric inflammation—an increase in inflammation in the corpus, and a decrease in the antrum. It is currently recommended to obtain biopsies from 3 different sites in patients who are actively using antireflux medication: 1 from the angularis, 1 from the greater curvature of the corpus, and 1 from the greater curvature of the antrum.

Biopsies from the corpus in this clinical scenario have been reported to increase detection of H. pylori by 10%.10 Warthin-Starry staining of antral biopsy has been described as the most sensitive and specific test to establish the presence of H. pylori.11 The main advantage of histologic testing is the direct visualization of pathologic changes associated with H. pylori infection, such as inflammation, atrophy, intestinal metaplasia, and malignancy. In the absence

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of detectable H. pylori, some pathologists accept the presence of these histopathologic findings as a surrogate marker of H. pylori infection.7 An important limitation of histology is that the use of some medications, such as bismuth, antibiotics, and proton pump inhibitors (PPIs), reduce the sensitivity and specificity of the test. Other limitations include cost and the need for experienced personnel. Rapid Urease Test RUT is used widely in clinical practice and exploits the action of the H. pylori urease enzyme. Urease promotes survival of H. pylori in the hostile acidic environment of the stomach by breaking down urea into carbon dioxide and ammonia. RUT detects active H. pylori infection in a gastric biopsy specimen using an agar gel or a reaction strip containing urea. A number of kits are commercially available in the United States and are comparable in overall performance, with some practical differences. The utility of RUT in clinical practice is compromised by the widespread use of PPIs, which can lead to falsenegative results. Studies suggest that patients should not take PPIs for 1 to 2 weeks before undergoing RUT for an optimal result.7 The test is a valuable option for patients who have not taken PPIs for at least 2 weeks before testing and who are undergoing endoscopy for other indications. Acute ulcer bleeding has been shown to decrease the sensitivity and negative predictive value of RUT.12-16 The test also is affected by the use of bismuth-containing compounds and antibiotics, which can decrease the efficacy of the test by up to 25%.17 Culture In addition to being a highly specific method of diagnosis, culture has the advantage of being able to provide antimicrobial sensitivities.18 Culture, however, is not as sensitive as histology or RUT, which are cheaper and more cost-effective methods of diagnosis.19,20 The patchy distribution of H. pylori in the stomach and the challenge of collecting an ideal biopsy sample make culture a particularly difficult diagnostic test. Additionally, some medications—including antibiotics, PPIs, bismuth, and sucralfate—should be avoided by patients before undergoing biopsy. In patients for whom a culture will be performed, antibiotics should be discontinued at least 28 days before obtaining a gastric specimen.18 Furthermore, the type of culture media or transport medium, as well as the processing of the specimen (eg, H. pylori is sensitive to drying), may interfere with the sensitivity of the culture.18,21 The culture test is of great value in patients who have failed treatment with standard antimicrobial therapy for H. pylori, and the results of the test can facilitate decisions about subsequent treatment regimens.

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Endoscopic Urea Breath Test In patients who require an upper endoscopy, E-UBT can be performed at the end of the procedure to test for H. pylori. For this test, urea labeled with 13-C is applied to the stomach through the working channel of the endoscope, and breath samples are collected before the procedure and up to 10 minutes after the application of the labeled urea.22 E-UBT avoids the possibility of contamination of test results with oral urease, and the reported accuracy of the test is 100%. However, the test is limited to use in patients with a clear indication for endoscopy.

NONINVASIVE TESTS Noninvasive tests for H. pylori include serology, UBT, and SAT. These tests are performed most often in the setting of pre-endoscopic screening of patients with functional dyspepsia and to test for eradication of H. pylori in patients who have undergone treatment.8 Serology Serologic testing is used to test for the presence of immunoglobulin G antibodies directed against H. pylori. This test is less expensive and is used more widely than other noninvasive diagnostic tests. The sensitivity and specificity of serology is reported at 85% and 79%, respectively.23 Serology is useful in the diagnosis of H. pylori in patients taking PPIs or other antireflux medications, those recently treated with antibiotics, and patients with upper gastrointestinal bleeding (UGIB), gastric atrophy, or gastric malignancy. It is the only test that is not affected by localized changes in the stomach that affect H. pylori load. Serologic testing is not suitable for the diagnosis of active H. pylori infection or as a follow-up test after H. pylori eradication therapy.24 Commercially available serologic tests are not equivalent and differ in accuracy. Only tests with accuracy greater than 90% should be used in clinical practice.7 Urea Breath Test UBT exploits the ability of H. pylori to convert urea into carbon dioxide. UBT measures the amount of carbon isotope—either radioactive 14-C or nonradioactive 13-C—present in exhaled carbon dioxide after the ingestion of labeled urea.25-28 Although the amount of radiation in radioactive 14-C is less than daily background radiation exposure, UBT with 13-C is preferred for children and pregnant women.7,25,26 The sensitivity and specificity of UBT commonly exceeds 95%, and the accuracy is similar to histology.28 Additionally, UBT is an excellent test for assessment of H. pylori eradication.26 UBT in patients on long-term PPI therapy may result


in false-negative results because PPI use leads to a rise in gastric pH and a subsequent reduction in H. pylori load.7 Several studies have shown false-negative rates of 10% to 40% with UBT in patients undergoing long-term treatment with PPIs.29,30 The current recommendation calls for patients undergoing UBT to discontinue PPIs at least 2 weeks before testing.7

quickly and accurately.40 Real-time PCR also is useful in identifying H. pylori infection in patients with UGIB.41 The sensitivity and specificity of real-time PCR in antral and corpus biopsies of patients with UGIB are reported to be higher than 80%, suggesting that the test may be useful in patients with low H. pylori loads, such as those with UGIB.41

Stool Antigen Test SAT identifies H. pylori antigen present in stool through the detection of monoclonal and polyclonal anti–H. pylori antibodies.8 Currently, 2 SATs are commercially available. One is a laboratory-based enzyme-linked immunosorbent assay (ELISA) and the other is a rapid, in-office immunochromatography test (ICT).7 A systematic review demonstrated high sensitivity, specificity, and positive and negative predictive values for the polyclonal SAT before eradication therapy; however, the sensitivity and positive predictive value of the polyclonal SAT declined significantly after eradication of H. pylori.31 The use of monoclonal antibodies (mAbs) helps to overcome this limitation. The accuracy of SAT is similar to UBT,7 and is greater than serology in patients with low pretest probability.31 A meta-analysis demonstrated that ELISA-based SAT using mAbs is highly accurate for the initial and post-treatment diagnosis of H. pylori.32 Conversely, the ICT-based SAT has limited accuracy.33,34 Current recommendations call for use of the ELISA-based SAT with a mAb reagent.7

Stool PCR Stool PCR may be a reliable and useful noninvasive tool for detection of H. pylori, as well as assessment of clarithromycin resistance.42 Multiplex PCR Multiplex PCR allows for the rapid detection of H. pylori infection as well as detection of vacA and cagA genotypes directly from gastric biopsy specimens. This assay does not require culturing of strains or extraction of DNA from biopsy samples, and is becoming a valuable tool for diagnosing H. pylori infection in developing countries.43 Multiplex PCR also is valuable in identifying resistance to clarithromycin, and in situations where real-time PCR cannot be performed.44,45 Currently, a dual-priming oligonucleotide–based multiplex PCR kit is commercially available to detect the mutations responsible for H. pylori clarithromycin resistance.44 Chen et al compared the diagnostic value of multiplex PCR and RUT for the detection of H. pylori infection in patients recently taking PPIs; multiplex PCR detected an additional 46.1% positive cases compared with RUT.46

MOLECULAR METHODS Molecular methods of H. pylori detection are based on the detection of specific sequences of H. pylori DNA using PCR or FISH.35 These methods can be used to detect H. pylori infection as well as antibiotic resistance in patients who have failed H. pylori eradication therapy and for whom cultures cannot be performed.7 Polymerase Chain Reaction PCR is an assay that uses rapid amplification of targeted sequences of H. pylori DNA to identify infection. The test is highly specific and may be more sensitive than other biopsy-based diagnostic techniques.8 PCR can be used to detect H. pylori in a variety of clinical samples, including gastric biopsy, gastric juice, saliva, dental plaque, and stool.36 PCR also offers a valuable method for identifying H. pylori mutations that are associated with antimicrobial resistance.37-39 PCR provides a rapid and highly accurate method of detection of clarithromycin resistance, and thus may help to decrease treatment failure rates.40 Real-Time PCR Real-time PCR can detect resistance to clarithromycin

Fluorescence In Situ Hybridization Peptide nucleic acid fluorescence in situ hybridization (PNA-FISH) is a new molecular test for the detection of H. pylori infection and for assessment of clarithromycin resistance using paraffin-embedded gastric biopsy specimens. PNA-FISH also allows direct and specific visualization of H. pylori. Compared with culture, the sensitivity and specificity of PNA-FISH are 84.2% and 90.9%, respectively.47 Compared with histology, the sensitivity and specificity of FISH are 97.9% and 100%, respectively.48 Additionally, the ability of FISH to measure clarithromycin resistance is a significant advantage of this test over histology.

Diagnostic Testing in Special Populations PEPTIC ULCER DISEASE H. pylori infection and use of NSAIDs are the main etiologic factors in PUD. Diagnosis and eradication of H. pylori decreases the rate of ulcer recurrence and significantly diminishes the risk for rebleeding. With the exception of serology, all diagnostic tests for H. pylori in patients with PUD demonstrate

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decreased sensitivity. Several reasons may explain this phenomenon, including exposure of the biopsy specimen to blood, the presence of anti–H. pylori antibodies, inhibition by serum enzymes, and removal of bacteria by gastric lavage. A metaanalysis demonstrated that biopsy-based diagnostic methods, such as histology, RUT, and culture, have a low sensitivity but a high specificity in patients with bleeding PUD. Among noninvasive diagnostic tests in patients with PUD, UBT has a high accuracy rate, whereas SAT is reportedly the least accurate method.16

GASTROESOPHAGEAL REFLUX DISEASE The relationship between H. pylori infection and gastroesophageal reflux disease (GERD) is controversial. Several studies have shown that H. pylori infection has no effect on GERD symptom severity, recurrence, and treatment efficacy. Furthermore, H. pylori eradication does not exacerbate preexisting GERD or affect treatment efficacy.7 Laine et al evaluated symptoms of erosive esophagitis or GERD in patients without a prior history of GERD who received treatment for H. pylori, as well as worsening symptoms of GERD in patients with prior symptomatic GERD. They found no evidence for the development of erosive esophagitis or new GERDrelated symptoms in patients without prior GERD undergoing H. pylori treatment, as well as no evidence of worsening of symptoms of GERD in patients with preexisting GERD after treatment for H. pylori.49 Additionally, H. pylori status has no reported effect on the long-term use of PPIs for maintenance therapy in patients with GERD.50

IRON DEFICIENCY ANEMIA AND IDIOPATHIC THROMBOCYTOPENIC PURPURA The Maastricht IV consensus reported that there is sufficient evidence to support the role of H. pylori infection in the etiology of unexplained IDA, ITP, and vitamin B12 deficiency.7 In these clinical scenarios, H. pylori should be sought and eradicated. Evidence supporting the development of IDA in patients with H. pylori infection suggests that chronic pan-gastritis results in achlorhydria, which reduces iron absorption in the proximal small bowel.8 Two recent meta-analyses support this hypothesis by demonstrating that H. pylori eradication is associated with an increase in hemoglobin levels in treated patients.51,52 H. pylori also has been shown to be an independent risk factor for the development of IDA in pediatric and adult patients.53,54 Whether it would be beneficial to test and treat H. pylori in all patients with unexplained IDA remains to be determined. Similar to the situation in patients with IDA, an increase in platelet count was reported in more than

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50% of patients with ITP who were successfully treated for H. pylori infection.55-57

USE OF NONSTEROIDAL ANTI-INFLAMMATORY DRUGS AND ACETYLSALICYLIC ACID H. pylori infection is associated with an increased risk for uncomplicated and complicated PUD in patients who are receiving NSAIDs and/or low-dose aspirin (acetylsalicylic acid; ASA).58 Eradication of H. pylori results in a significant reduction in risk for PUD that is associated with either NSAID or low-dose ASA use. Furthermore, H. pylori eradication is beneficial before starting NSAID treatment, and it should be strongly considered in patients with a history of PUD.7

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27. Steen T, Berstad K, Meling T, Berstad A. Reproducibility of the 14C urea breath test repeated after 1 week. Am J Gastroenterol. 1995;90(12):2103-2105. 28. Leodolter A, Dominguez-Munoz JE, von Arnim U, et al. Validity of a modified 13C-urea breath test for pre- and posttreatment diagnosis of Helicobacter pylori infection in the routine clinical setting. Am J Gastroenterol. 1999;94(8):2100-2104. 29. Levine A, Shevah O, Shabat-Sehayek V, et al. Masking of 13C urea breath test by proton pump inhibitors is dependent on type of medication: comparison between omeprazole, pantoprazole, lansoprazole and esomeprazole. Aliment Pharmacol Ther. 2004;20(1):117-122. 30. Ozturk E, Yesilova Z, Ilgan S, Ozguven M, Dagalp K. Performance of acidified 14C-urea capsule breath test during pantoprazole and ranitidine treatment. J Gastroenterol Hepatol. 2009;24(7):1248-1251. 31. Gisbert JP, Pajares JM. Stool antigen test for the diagnosis of Helicobacter pylori infection: a systematic review. Helicobacter. 2004;9(4):347-368. 32. Gisbert JP, de la Morena F, Abraira V. Accuracy of monoclonal stool antigen test for the diagnosis of H. pylori infection: a systematic review and meta-analysis. Am J Gastroenterol. 2006;101(8):1921-1930. 33. Calvet X, Lario S, Ramirez-Lazaro MJ, et al. Accuracy of monoclonal stool tests for determining cure of Helicobacter pylori infection after treatment. Helicobacter. 2010;15(3):201-205.

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50. Klinkenberg-Knol EC, Nelis F, Dent J, et al. Long-term omeprazole treatment in resistant gastroesophageal reflux disease: efficacy, safety, and influence on gastric mucosa. Gastroenterology. 2000;118(4):661-669. 51. Muhsen K, Cohen D. Helicobacter pylori infection and iron stores: a systematic review and meta-analysis. Helicobacter. 2008;13(5):323-340. 52. Qu XH, Huang XL, Xiong P, et al. Does Helicobacter pylori infection play a role in iron deficiency anemia? A meta-analysis. World J Gastroenterol. 2010;16(7):886-896. 53. Baggett HC, Parkinson AJ, Muth PT, et al. Endemic iron deficiency associated with Helicobacter pylori infection among school-aged children in Alaska. Pediatrics. 2006;117(3):e396-e404. 54. Cardenas VM, Mulla ZD, Ortiz M, et al. Iron deficiency and Helicobacter pylori infection in the United States. Am J Epidemiol. 2006;163(2):127-134. 55. Pellicano R, Franceschi F, Saracco G, et al. Helicobacters and extragastric diseases. Helicobacter. 2009;14(Suppl 1):58-68. 56. Arnold DM, Bernotas A, Nazi I, et al. Platelet count response to H. pylori treatment in patients with immune thrombocytopenic purpura with and without H. pylori infection: a systematic review. Haematologica. 2009;94(6):850-856.

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57. George JN. Definition, diagnosis and treatment of immune thrombocytopenic purpura. Haematologica. 2009;94(6):759-762. 58. Huang JQ, Sridhar S, Hunt RH. Role of Helicobacter pylori infection and non-steroidal anti-inflammatory drugs in peptic-ulcer disease: a meta-analysis. Lancet. 2002;359(9300):14-22. 59. Peek RM Jr, Fiske C, Wilson KT. Role of innate immunity in Helicobacter pylori-induced gastric malignancy. Physiol Rev. 2010;90(3):831-858. 60. Vakil N, Rhew D, Soll A, Ofman JJ. The cost-effectiveness of diagnostic testing strategies for Helicobacter pylori. Am J Gastroenterol. 2000;95(7):1691-1698. DISCLAIMERâ&#x20AC;&#x201D;This review is designed to be a summary of information and represents the opinions of the author. Although detailed, the review is not exhaustive. Readers are strongly urged to consult any relevant primary literature, the complete prescribing information available in the package insert of each drug, and the appropriate clinical protocols. No liability will be assumed for the use of this review, and the absence of typographical errors is not guaranteed. Copyright Š 2013, McMahon Publishing, 545 West 45th Street, 8th Floor, New York, NY 10036. Printed in the USA. All rights reserved, including right of reproduction, in whole or in part, in any form.


August 2013