May 2015 by McMahon Group

Pl At eas Bo th e Vi ot e sit h D U #2 D s 14 W 9

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H E PAT O L O G Y

FOCUS

HCV Vaccine Efforts Proceeding With Promise

recently published study in the Journal of Virologyy has reinforced hopes that a vaccine for the hepatitis C virus (HCV) is possible by demonstrating that a vaccine derived from a single strain of the virus can elicit antibodies that target multiple strains. Had such a universal HCV vaccine already existed, it might have prevented more than 70,000 reported see Vaccine, page 22

Hep B Testing And Treatment Shortchanging Vets BOSTON—Both the testing for and treatment of hepatitis B infection in the United States is inadequate, according to an analysis of data from the Veterans Health Administration (VHA). see VA, page 34

Are Medical Homes The Future of IBD Care? are? ?

esearchers are eagerly observing two recently launched medical homes for the treatment of inflammatoryy bowel disease (IBD) to see if the modelss could become the standard of care for patients with the condition. The medical home approach staands to improve IBD outcomes and simultan neously reduce the use and cost of health caare, said John Allen, MD, MBA, presidentt of the American Gastroenterological Assoociation. “This is a very exciting path to be going down,” said Dr. Allen, clinical chiief of gastroenterology and hepatology at the Yale School of Medicine, in New Haven n, Conn. “The current health care envirronment requires gastroenterologists and oth her providers to collaborate and address all of the aspects of our IBD patients’ health, and the mediical home model is one way to do so.” The need for greater collaboratioon is due to a shift from traditional fee-for-service reimbursement b t tto shared h d savings models, bundled payments and outcomes-based care, said Dr. Allen, who is not involved in either of the model initiatives. “Under the medical home model, gastroenterologists assume clinical and sometimes financial responsibility for their IBD patients and coordinate care with other specialists,” he said.

Manipulating the Microbiome Produces Hope, but Uneven Results

UPMC Model Stresses Multidisciplinary Care The multidisciplinary University of Pittsburgh Medical Center (UPMC) IBD medical home, launched in March, puts a strong emphasis on see Home, page 54

I N S I D E

The MD’s guide to hedge fund investing........page 6

PHILADELPHIA—Intestinal dysbiosis, or microbial imbalance, is associated with a host of intestinal and systemic diseases such as autoimmune conditions, obesity and metabolic disorders. In recent years, researchers have poured considerable energy into studying therapeutic interventions such as diet, probiotics, antibiotics and fecal transplants that target the gut microbiota, and although the field is young, it is becoming clearer what those interventions can do for gastrointestinal (GI) ailments. “Manipulation of the microbiota is still in its infancy, but I look forward to an explosion of data in the next decade on this topic,” said Mark H. Mellow, MD, emeritus director of Integris Digestive Health Center, in Oklahoma City.

CMV no innocent bystander in UC .................page 14 HEPATOLOGY

I N

FOCUS

Aspirin users may ward off NAFLD ............page 32 Adoption of NAFLD guidelines spotty y ......page 36

see Interventions, page 62 THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Driving Patient Safety With Endoscopic Tattooing Faculty

OPT IN

Douglas K. Rex, MD, MACP, MACG, FASGE, AGAF

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Distinguished Professor of Medicine Indiana University School of Medicine Chancellor’s Professor Indiana University Purdue University Indianapolis Director of Endoscopy Indiana University Hospital Indianapolis, Indiana

Introduction

Driving Patient Safety With Endoscopic Tattooing see page 20

The 1999 Institute of Medicine report found that preventable medical errors, including wrong-site surgery, caused 44,000 to 98,000 deaths each year, with an associated annual cost of $17 billion to $29 billion.1-3 Even using the conservative estimate, this placed medical errors among the leading causes of death in the United States. Fortunately, safeguards instituted over the past decade have resulted in the reduction of preventable medical errors. This article will discuss the issue of wrong-site surgery in patients with gastrointestinal (GI) disease and the role of endoscopic tattooing in reducing this devastating error in care.

Wrong-Site Surgery in Patients With Endoscopically Defined GI Disease Wrong-site surgery encompasses surgery performed on the wrong side of the body, wrong surgical site, wrong surgical procedure performed, and surgery performed on the wrong patient.4 Wrong-site surgery is also defined as a sentinel event (ie, an unexpected occurrence involving death or serious physical or psychological injuries, or the risk thereof) by the Joint Commission, which found wrong-site surgeries to be the third highest-ranking event among sentinel events.5 The issue of wrong-site surgery is particularly relevant to GI lesions that are identified endoscopically with subsequent referral for surgery. Indeed, the intraoperative identification of lesions previously detected by endoscopy often is difficult, particularly during laparoscopic surgery.6 Estimation of the tumor site at colonoscopy can be imprecise, with as many as 14% of tumor locations incorrectly identified.7 The lack of accurate lesion identification during laparoscopy may lead to resection of the wrong bowel segment.8 Wrong-site surgery is generally caused by a lack of a formal system to verify the surgical site or a breakdown of the system that verifies the correct site. The Joint Commission Center for Transforming Healthcare estimates that approximately 80% of serious medical errors, including wrong-site surgery, involve miscommunication

between caregivers when patients are transferred or handed off.9 This suggests that an objective system for passing information between the endoscopist and the surgeon is critical to avoid wrong-site surgery for patients with endoscopically identified lesions.

Endoscopic Tattooing for the Prevention Of Wrong-Site Surgery The Joint Commission recommends marking the procedure site as a prime mode of avoiding wrong-site surgery. This step serves as a durable and accurate means of communicating the location of the GI lesion between the endoscopist and the surgeon. Although traditional surgical site marking, for example during orthopedic surgery, is done by marking the surgical site on the affected limb, this avenue is obviously not applicable to marking lesions of the GI tract.10 The safety and efficacy of endoscopic tattooing has been examined in clinical studies. Whereas early endoscopic markers, such as India ink, contained impurities such as shellacs, phenols, ammonia, and animal products that could cause inflammatory reactions, modern endoscopic markers are composed of high-purity suspended carbon particles that do not have these adverse effects.11 For example, Askin and colleagues studied the use of Spot (GI Supply, Camp Hill, PA) for endoscopic tattooing in 113 patients and reported that none of the patients developed fever, abdominal pain, or signs or symptoms of inflammation.12 Ten patients with colon polyps deemed endoscopically unresectable or malignant had the area surrounding the lesions tattooed and subsequently underwent surgical resection. At operation, the tattoos were visible in all cases, and none of the resected specimens exhibited necrosis or abscess formation on histopathology.12 An additional 103 patients underwent colonoscopic tattooing and then underwent colonoscopy or surgery at another hospital. In the 42 patients who underwent subsequent colonoscopy 3 to 12 months after tattooing, all tattoos were readily identifiable.12 Injection of appropriately diluted and sterile marker solutions is generally safe, with most complications related to transmural injection. In a retrospective study, 195 patients were tattooed in the 4 quadrants surrounding their lesions with 0.2- to 0.5-mL marker aliquots of India ink. No short-term complications were reported. Surgeons who used endoscopic tattooing for visualization in colectomies found that the dye was helpful in identifying the area of resection during surgery.13 A retrospective analysis of approximately 444 cases of colonic tattooing using various preparations found a complication in only 1 patient in whom abdominal pain, tenderness, and fever developed after tattooing a cautery-induced ulcer.14 Without proper visualization, tumors may be missed. Vignati and colleagues noted in 320 patients that 37

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

locations noted were incorrect, 7 cancers were missed and discovered at the time of surgery, and in 24 instances the surgeon had difficulty locating the lesion.7 Planned laparoscopic colorectal resection may require conversion to an open procedure in up to 14.3% of cases.15 Patients who convert to open resection may experience greater blood loss, longer length of hospital stay, and a longer time to first bowel movement after surgery.16 Tattooing is valuable with rectal polyps, but in 1 series was seldom performed after resection of large and even malignant polyps. For incompletely resected polyps, tattooing made identification of the polypectomy site easier during follow-up examinations. For malignant polyps, tattooing facilitated surgical resection, whether performed by the transanal approach or by low anterior resection, and particularly for laparoscopic resections. In general, tattooing of large and potentially malignant polyps at the original endoscopic procedure prevented the need for additional endoscopy to tattoo the site for surgery when cancer was identified by the pathologist; tattooing helped to limit the extent of some resections.17

Spotlight on hospital malnutrition (Part 1 of 2) ............................................................page 50

Guidelines As a result of these and other studies, as well as extensive anecdotal experience, the 2014 American Society for Gastrointestinal Endoscopy (ASGE)/American College of Gastroenterology (ACG)’s quality indicators for colonoscopy suggest that “both benign and malignant lesions sent for surgical resection that are not in an area that can be identified with certainty by endoscopy (eg, the cecum and proximal ascending colon where the cecum is still endoscopically visible) and the rectum should be marked with ample submucosal injection of carbon black in 3 to 4 quadrants to ensure resection of the correct segment. If the tattoo cannot be located during surgery, intraoperative colonoscopy is needed to resolve the correct location” (Figure 1).18

Figure 1. A 3-quadrant tattoo marking for surgery at the distal end of involvement in a patient with severe serrated polyposis. Image courtesy of Douglas Rex, MD, MACP, MACG, FASGE, AGAF.

Survey turns up weaknesses in care of pediatric celiac disease .......................page 66

1 MOST PRESCRIBED,

BRANDED BOWEL PREP KIT1

A CLEAN SWEEP

EFFECTIVE RESULTS IN ALL COLON SEGMENTS >90% no residual stool in all colon segments compared to Standard 4-Liter Prep2*†‡ · These results were statistically significant in the cecum (P=.010)2*§ · Significantly more subjects in SUPREP® group had no residual fluid in 4 out of 5 colon segments2*‡ Help meet Gastroenterology Quality Improvement Consortium (GIQuIC) benchmarks for 85% quality cleansing3 with the split-dose efficacy of SUPREP ® Bowel Prep Kit.4 *This clinical trial was not included in the product labeling. †Standard 4-Liter Prep [sulfate-free PEG electrolyte lavage solution]. ‡Based on investigator grading. §Statistically significant difference. References: 1. IMS Health, NPA Weekly, March 2015. 2. Rex DK, Di Palma JA, Rodriguez R, McGowan J, Cleveland M. A randomized clinical study comparing reduced-volume oral sulfate solution with standard 4-liter sulfate-free electrolyte lavage solution as preparation for colonoscopy. Gastrointest Endosc. 2010;72(2):328-336. 3. Rex DK, Schoenfeld PS, Cohen J, et al. Quality indicators for colonoscopy. Gastrointest Endosc. 2015;81(1):31-53. 4. SUPREP Bowel Prep Kit [package insert]. Braintree, MA: Braintree Laboratories, Inc; 2012.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

Multidrug-Resistant Shigellosis On Rise in the United States New infections emphasize importance of using antibiotics wisely

nternational travelers return with all kinds of souvenirs, but the Centers for Disease Control and Prevention (CDC) said they also are bringing back a multidrug-resistant intestinal illness that is spreading throughout the country. Researchers at the CDC found that

Shigella sonneii bacteria resistant to the antibiotic ciprofloxacin were introduced repeatedly as ill travelers returned from overseas, causing a series of outbreaks of shigellosis between May 2014 and February 2015. To date, 243 individuals in 32 states and Puerto Rico have been infected

(MMWR 2015;64:318-320). Ciprofloxacin is the first choice to treat shigellosis among U.S. adults. Until recently, ciprofloxacin resistance has occurred in just 2% of Shigella infections tested in the United States, but was found in 90% of samples tested in the

IMPORTANT SAFETY INFORMATION SUPREP® Bowel Prep Kit (sodium sulfate, potassium sulfate and magnesium sulfate) Oral Solution is an osmotic laxative 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 the kit. Use caution when prescribing for patients with a history of seizures, arrhythmias, impaired gag reflex, regurgitation or aspiration, severe active ulcerative colitis, impaired renal function or patients taking medications that may affect renal function or electrolytes. Use can cause temporary elevations in uric acid. Uric acid fluctuations in patients with gout may precipitate an acute flare. 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 a final volume of 16 ounces and ingestion of additional water as recommended is important to patient tolerance.

BRIEF SUMMARY: Before prescribing, please see full Prescribing Information and Medication Guide for SUPREP® Bowel Prep Kit (sodium sulfate, potassium sulfate and magnesium sulfate) Oral Solution. INDICATIONS AND USAGE: An osmotic laxative 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: SUPREP Bowel Prep Kit is an osmotic laxative 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 components of the kit. Use caution when prescribing for patients with a history of seizures, arrhythmias, impaired gag reflex, regurgitation or aspiration, severe active ulcerative colitis, impaired renal function or patients taking medications that may affect renal function or electrolytes. Pre-dose and post-colonoscopy ECG’s should be considered in patients at increased risk of serious cardiac arrhythmias. Use can cause temporary elevations in uric acid. Uric acid fluctuations in patients with gout may precipitate an acute flare. 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 a final volume of 16 ounces and ingestion of additional water as recommended is important to patient tolerance. 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 375 patients who took SUPREP Bowel Prep Kit in clinical trials, 94 (25%) were 65 years of age or older, while 25 (7%) were 75 years of age or older. No overall differences in safety or effectiveness of SUPREP Bowel Prep Kit administered as a split-dose (2-day) regimen were observed between geriatric patients and younger patients. DRUG INTERACTIONS: Oral medication administered within one hour of the start of administration of SUPREP may not be absorbed completely. ADVERSE REACTIONS: Most common adverse reactions (>2%) are overall discomfort, abdominal distention, abdominal pain, nausea, vomiting and headache. Oral Administration: Split-Dose (Two-Day) Regimen: Early in the evening prior to the colonoscopy: Pour the contents of one bottle of SUPREP Bowel Prep Kit into the mixing container provided. Fill the container with water to the 16 ounce fill line, and drink the entire amount. Drink two additional containers filled to the 16 ounce line with water over the next hour. Consume only a light breakfast or have only clear liquids on the day before colonoscopy. Day of Colonoscopy (10 to 12 hours after the evening dose): Pour the contents of the second SUPREP Bowel Prep Kit into the mixing container provided. Fill the container with water to the 16 ounce fill line, and drink the entire amount. Drink two additional containers filled to the 16 ounce line with water over the next hour. Complete all SUPREP Bowel Prep Kit and required water at least two hours prior to colonoscopy. Consume only clear liquids until after the 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.suprepkit.com

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March 2015

recent clusters that occurred in Massachusetts, California and Pennsylvania. Shigellosis can spread very quickly in groups such as children in child care facilities, homeless people and gay and bisexual men, as occurred in these outbreaks. “These outbreaks show a troubling trend in Shigellaa infections in the United States,” said CDC Director Tom Frieden, MD, MPH. “Drug-resistant infections are harder to treat and because Shigellaa spreads so easily between people, the potential for more—and larger—outbreaks is a real concern. We’re moving quickly to implement a national strategy to curb antibiotic resistance because we can’t take for granted that we’ll always have the drugs we need to fight common infections.” In the United States, most Shigellaa is already resistant to the antibiotics ampicillin and trimethoprim/sulfamethoxazole. Globally, Shigella’ss resistance to ciprofloxacin is increasing. The broad-spectrum quinolone antibiotic is often prescribed to people who travel internationally, in case they develop diarrhea while abroad. More study is needed to determine what role, if any, the use of antibiotics during travel may have in increasing the risk for antibiotic-resistant diarrheal infections among returned travelers. “The increase in drug-resistant Shigella makes it even more critical to prevent shigellosis from spreading,” said Anna Bowen, MD, MPH, a medical officer in CDC’s Waterborne Diseases Prevention Branch and the lead author of the study. The CDC’s PulseNet laboratory network identified an increase in S. sonnei infections with an uncommon genetic fingerprint in December 2014. Further testing at the CDC’s National Antimicrobial Resistance Monitoring System (NARMS) lab found that the bacteria were resistant to ciprofloxacin. PulseNet detected several large clusters: 45 cases in Massachusetts, 25 cases in California and 18 cases in Pennsylvania. About half of the PulseNet cases with patient information were associated with international travel, mostly to the Dominican Republic and India. The San Francisco Department of Public Health reported another 95 cases, with almost half occurring among the homeless or individuals living in single-room occupancy hotels. Shigellaa causes an estimated 500,000 cases of diarrhea in the United States every year. It spreads easily and rapidly from person to person and through contaminated food and recreational water see Shigella, page 7

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

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Heard Here First See page 28

In 2015, no cancer patients should be cured of their malignancy, only to die from reactivation of hepatitis B virus.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

There Are No 50-Cent nt Dollars An insider’s guide to hedge-fund investing

few years ago, I had minor surgery on my eyelid. As the dermatologist hovered over my face with a scalpel, he asked me about my work as manager of a hedge fund. When someone has the power to blind me in an instant, I prioritize agreeability over thoughtfulness. But when he bragged that he was about to invest in a particular hedge fund, I couldn’t help but pooh-pooh the idea. Before I barely made a living as a writer, I was the client-facing guy for big hedge funds. In fact, two became the largest in the world over the course of my tenure. For the last five years of that run, I also sat on the investment committee of a multibillion-dollar university endowment. My remit: to help them select hedge funds.a Over the past two decades, I have also been an active hedge fund investor myself (with decent results). In the doctor’s case, he was excited to be investing in his first hedge fund—one of the big boys. Unfortunately, in this case, it was bound to be a dud. A famous manager with a phenomenal track record, one so exceptional that he would no longer accept new money, was opening a so-called “hedge fund light” for high net-worth investors; that is, a similar but watered-down version of his marquee strategy. So while not engaging his original lucrative approach, the manager’s fundraise was benefiting from his sterling reputation. Why doesn’t hedge fund light work? For the same reason Bud Light doesn’t work for me. You effectively take something good (beer, not Budweiser necessarily), pump it up with costless filler (water) and your result, to my taste buds, at least, is something not remotely satisfying. In the case of hedge funds, the filler is your manager’s next-best ideas and instead of calorie avoidance, your binding constraint is capacity. In the world of hedge funds, capacity is the key. Yet, hedge fund managers get squirrelly when you ask them about it. Their “I haven’t noticed it” act is as convincing as their dates’ when the check arrives at French Laundry. As a hedge fund manager’s investment strategy nears capacity, it becomes harder for them to find great trades or investments, ones that will “move the needle” given their current size. When I managed a $100 million fund, a trading opportunity that yielded $1 million was a good week’s work. As the portfolio surpassed $1 billion under management, the $1 million idea was no longer worth the effort.

Beware Managers Who Won’t Admit Capacity There is a strong disincentive to even acknowledge that you have reached capacity. Such an admission means you will forgo your juicy 2% management fee. Good managers admit capacity because they don’t want

to compromise future trading profits. Such conviction is good. It also usually means the manager has a shipload of his or her own money in the fund. But in the world of alpha—making money from skill rather than just generating the returns that the broad market gives you—there aren’t great ideas and slightly less great ideas. For every terrific manager I’ve ever met, it’s either flashes of brilliance—or the market return. We pay managers for the special and differentiated ideas. Moreover, and this is a hard one to swallow, we pay them to do nothing when an opportunity isn’t special. So the hedge fund light is a unicorn: It has the allure of convincing hair replacement, but there’s simply no such thing. Think about it this way: I’ve found a particular bond, let’s call it Piñatas Unlimited Series T (PUNT) that trades at 50 cents on the dollar due to the global decline in piñata sales. All Piñata bonds are performing poorly, but only Series T has a special covenant guaranteeing that in the event of a default, all of the assets of Piñatas’ wellcapitalized parent corporation, MegaCorp, back the bond. No one else knows this because Series T is an obscure issue (the documents are not available online). So I’ve found the holy grail here, a 50-cent dollar. Here’s the catch: Piñatas only issued $10 million of Series T. As a greedy hedge fund manager, I want alll of them. My $100 million original fund buys the entire outstanding, a 5% position. If Piñatas’ bonds recover, we make a 5% profit, but even our worst-case results in a similar profit due to the guarantee. Unfortunately, my new fund can’t also get in on PUNTs. It buys the optically similar Series A, which is like any other distressed bond. No unique insight on that one; any investor can get this exposure cheaply from a high-yield bond mutual fund for about 0.5% in annual fees (about 15% of the cost of a typical hedge fund). This is an example of a distressed hedge fund, but it

holds true for merger arbitrage funds or even quantitative funds. Generally, hedge fund managers want to operate in the corners of markets, far from crowds. Thus, generally, hedge funds that are designed to manage tens of billions of dollars while accepting inflows and outflows every day are not really hedge funds, in my mind. So I told my doctor not to invest, and he told me to wear sunblock when I was 7. As of this writing, that fund has lost money, albeit very consistently, and to illustrate my point has trailed the manager’s original fund by about 15% per year. ... Over the rest of this series, I will discuss other aspects of alternative investing, including: • Hedge fund categories (including CTAs) • Sure, stocks are more fun to talk about, but is boring better? • Are hedge fund fees fair? (It depends on what your definition of “fair” is.) • Is it possible to care too much? Stop checking your results! • Celebrity managers. (Real managers don’t talk about their best ideas on television; only a precious few can generate alpha. If the manager writes amusing grandiloquent letters about why the market is wrong and he’s right, buy his letter, not his fund.) • Warren G. Hardings —Joe De Luca Mr. De Luca is a writer, and former hedge fund executive, in Montclair, N.J. a Trustees for large endowments are typically appointed because they have donated. Inheriting wealth (or accumulating it by inventing a comforter with sleeves) does not necessarily mean that one is a savvy investor or advisor.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

Do You Make This Mistake Concerning Customer Value?

magine! A “celebrity” economist stymied by the fact that a medical procedure, a hip replacement, for example, costs an insurer $X if performed at one facility, yet $X + $Y if done at another. His assumption: Some providers are just better at negoMark F. Weiss, tiating than others—and that that was JD somehow “unfair.” My guess is that he’d be happy if the government simply deemed the price, and happier still if he were the czar appointed to do the deeming. I’m sure I’m not the first to point out that economics is not a science and that celebrity economists are simply a subset of entertainers, but I’m left to wonder whether our economist ever thought about why one fast food place sells a mediocre burger for a dollar or two, while a few blocks away, Chez Whatever prices a slightly larger one at 13 times more and sells them like, well, hotcakes. We’re talking the same beef, too, not some exotic breed that’s fed craft beer twice a day and regularly attended to by licensed massage therapists. Getting back to hip replacement, certainly, some facilities might deploy better negotiation techniques than a multibillion-dollar insurer. But there are several larger, and more likely, things going on here, such as location and reputation—the carrier simply has to have those facilities and its associated providers on its panel. For physicians, the lesson to be drawn is the importance of developing what I call an Experience Monopoly, providing such a valuable experience to patients, referral sources and facilities that they deem you their preferred partner, one that they can’t see themselves doing without. You’ve deemed many businesses with this status yourself—perhaps the dry cleaner who always greets you by name and helps you carry your clothes to your car, or the restaurant with the wonderful outdoor heated patio (heated floor, large wood-burning fireplace and radiant heat lamps), delicious cuisine and incredibly attentive service, that you both frequent and recommend to everyone (contact me, I’ll give you its name). Although an Experience Monopoly is a “soft” concept, for the economists in the crowd there’s a way to describe its strength in the language of math: • E + Phe + PQenv = Strength of Unique Experience, where: • E = actual level of medical expertise and skill. • Phe = strength of the perceived human experience. • PQenv = degree of the perceived quality of the environment. Although I said I was writing in math, be warned that this is not a formula like 2+2 = 4. Unlike our economist

Shigella continued from page 3

use. It can cause watery or bloody diarrhea, abdominal pain, fever and malaise. Although diarrhea caused by Shigellaa typically resolves without treatment, individuals with mild illnesses are often treated with antibiotics to stop the diarrhea faster. Because ciprofloxacin-resistant Shigellaa is spreading, the CDC recommends that doctors test for resistance before

friends, I am not pretending that fluid circumstances and subjective determinations can lead to an actual equation that can be proven and repeated with scientific accuracy. Rather, it’s just the view from another perspective, describing the relationship among the factors that lead to an Experience Monopoly in your practice.

the environment: low. Perceived human experience factor: dismal. Strength of unique experience: zero, or perhaps even negative. Of course, the goal is for you to increase the level of performance within your medical group across each of the components. Note especially that you must focus on the

For example, a physician with a very acceptable level of expertise, say, 7 on a scale of 10, who delivers a fantastic experience from a bright, cheery, modern office, may have a far more successful practice in terms of patient satisfaction than an extremely competent physician, a 10 out of 10 in terms of expertise, who delivers a dismally perceived human experience in an unwelcoming atmosphere. Particularly important is an understanding that the environmental factor does not refer simply to the physical environment, over which, in some settings, you may have little to no control—it also refers to the relationship environment in which you provide services. Years ago, I developed a bump on my right wrist. I asked several physician-clients to recommend a hand surgeon. They all suggested Dr. X. I made an appointment with Dr. X. When I arrived to see him, I was shown into a small exam room, really only enough space for two simple chairs and a small table in between. After sitting for at least 20 minutes twiddling my thumb (the other one hurt too much to twiddle), with not a single magazine to read in sight, not even a six-monthold issue of “Good Housekeeping,” in walked Dr. X. Without introducing himself, he sat down, manipulated my wrist, and said, “Our opinion is that you have a ganglion cyst.” Never one to be shy, I pretended to look all around the minuscule room and then asked him, “Excuse me, but do you see anyone else in here?” I did have the surgery and, although it’s been more than 20 years, I have not had a problem with my wrist since. But have I ever recommended Dr. X to anyone? No way! Professional expertise: excellent. Perceived quality of

human experience and environmental factors. All physicians understand the importance of medical expertise. Yet that expertise alone, and, certainly, that expertise tamped down by the impact of a poor environment and an even poorer experience, is worthless in terms of creating relationships with patients, referral sources and facilities that over a career will prove extremely valuable. That’s the case not only in terms of the strength of those relationships, but also in connection with the impact those relationships will have on the perception of quality for purposes of “value-based purchasing” as advocated by both Medicare and private payors. And last, there’s the issue of price, the element that attracted the economist’s comments in the first place. Experience monopolies don’t exist in a vacuum. They are dependent on the value that your customer, whether it’s a hospital, a referral source or a patient, places on them. In other words, pricing, or value, is determined at the customer level. Simply put, some customers will not place as much value on your offering as others. The challenge is providing the level of experience that your targeted customers value. Wendy’s and Shake Shack don’t target the same customer, and neither should you. —Mark F. Weiss, JD

prescribing an antibiotic. Antibiotics may not even be needed, the CDC said. In the United States, the CDC suggested these actions to prevent the spread of shigellosis: • Hand washing with soap and water, especially after using the toilet and before preparing food or eating; • Keeping children home from child care and other group activities while

Mark F. Weiss, JD, is an attorney who specializes in the business and legal issues affecting physicians and physician groups on a national basis. He served as a clinical assistant professor of anesthesiology at USC Keck School of Medicine and practices with The Mark F. Weiss Law Firm, a firm with offices in Dallas, Los Angeles and Santa Barbara, Calif., representing clients across the country. He can be reached by email at markweiss@advisorylawgroup.com.

they are sick with diarrhea; Avoiding preparation of food for others while ill with diarrhea; • Avoiding swimming for a few weeks after recovering: and • Improving access to toilets and soap and water for washing hands among the homeless. Travelers to developing countries can take additional precautions to avoid diarrhea and minimize infection with •

resistant bacteria. Download the CDC’s app “Can I Eat This?” (http/::wwwnc.cdc. gov:travel:page:apps-about) to help make safer food and beverage choices. Wash hands frequently. Take bismuth subsalicylate to prevent travelers’ diarrhea, and if it occurs, treat it with over-the-counter drugs such as bismuth subsalicylate or loperamide. Try to restrict use of antibiotics to severe cases of travelers’ diarrhea. —GEN Staff

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

You Are as Smart as Your Patients

hysicians often live in a self-contained bubble in which our image in the medical community depends predominantly on our personal and social relationships with our peers and referring clinicians, and where our status in the hospital emanates from the volume of procedures we perform, assuming a reasonable safety profile. Patients have always been handed down our recommendations as the only path to better health. This physician-centric world belongs to the past, and the future one being charted in front of our eyes is governed by new rules that use words like “patient experience,” “engagement,” “patient-centered” and “value-based.”

relationship (http://www.ncrponline.org/ PDFs/2009/Thomson_Reuters_White_ Paper_on_Healthcare_Waste.pdf ). When it comes to surgery, my specialty, it is all about the 30% unnecessary procedures and how to improve on that ominous number; and yes, it is 30%! The first response by the system trying to reduce the excess and cost was to reduce reimbursement, but that led to more operative procedures and unnecessary care, since we all have heard and used the statement,

“you now have to see more patients and work harder to make the same money!” Every dollar spent in health care follows an “encounter,” which ends with a physician “order” and the cost related to the treatment prescribed, and this is where the 30% excess cost is generated. That certainly does not mean that 30% of physicians’ recommendations are self-serving, and a deeper look into how we physicians handle decision making and how we communicate it to patients explains how the

problem is caused, and proposes a natural solution. This solution is embodied by the new buzzword, “patient-centric medicine.” For many medical conditions for which there is more than one medically accepted treatment option, the medical literature is inconclusive or physicians disagree about which option is better. These conditions are referred to as “preference-sensitive” and include the care of nonemergent heart conditions, spine and joint surgery, many cancer treatments, cesarean delivery

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FREE iPad App Explore the features of the new app on your iPad. Three ways to download: 1. Go to the iTunes App Store and search for Gastroenterology & Endoscopy News. 2. Go to gastroendonews.com/apps and click on the “Available on the App Store” icon. 3. Scan this QR code with your iPad and download the App from iTunes. This new world, outlined by the language of health care reform, was born out of the exorbitant cost of the status quo, a cost that was not matched with the quality that other less expensive systems provided. The 2009 white paper by Thomson Reuters’s Robert Kelley, outlining where the $700 billion yearly waste in the U.S. health care system is spent, was a pivotal document for the lawmakers writing the Accountable Care Act (ACA). It is a mustread document for every physician who feels that we are subjected to an outside intrusion into the sacred physician–patient

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OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

and many vascular surgical conditions. In a physician-centric model, we physicians are trained to decide for the patient. That decision is filtered by the bias and experience of the doctor, his medical community allegiances and, obviously, financial interests. The hallmarks of preferencesensitive care are geographic variation and a trend that favors the expensive treatments. As an example, a patient with a heart condition could be twice more likely to get open-heart surgery in one city or four times more likely to get a coronary stent in another, while he is unlikely to be

informed that medical therapy could be as effective as both for his condition. What is obvious is that the physician making the decision is more likely to pick an option that works for him or her rather than one that fits with the personal choice and values of the patient, as long as both are defensible and within the “standard of care.” As a matter of fact, the Cochrane review of decision aid support suggests that providing the patient with decision support tools, such as pamphlets or videos, leads to significantly less elective operations with higher patient satisfaction

with the decision-making process and care, and no worsening of outcomes (Cochrane Database Syst Rev v 2014 Jan 28;1:CD001431. doi: 10.1002/14651858. CD001431.pub4.). The conclusion is that educating the patient will lead to a happier, more satisfied one, a patient who will also cost us less to attend to. The ACA thus mandates that we implement “shared decision-making,” which translates into the process of informing the patient about the existence of a choice, and rather than choosing for him, providing him with the tools to make

that choice. Unfortunately, the acceptance of this change in paradigm has been slow in the medical community and more needs to be done (N Engl J Medd 2013;368:6-8). Although the ACA tells us where we need to be, it is not clear about how we should go there. Why would a surgeon want to engage in shared decision making, a process that costs time and resources and can lead to fewer operations? Where is the carrot? The carrot is the fact that if you engage in patient education that leads to fewer see Bubble, page 10

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

Bubble continued from page 9

operations, you will get paid more for the operations that you do, and this is how it works: Your patient is now given surveys that measure his experience in his visits with you. The most commonly used family of surveys, the Consumer Assessment of Health Providers and Systems (CAHPS), asks patients questions about whether you provided them with educational material, gave them time to ask questions, listened to them, made them

feel you were in a hurry and other questions about your practice such as waiting time, staff professionalism and others. The responses to these surveys, now used routinely by payors, will place you in a tier according to your patients’ aggregate experience. These tiers are the main tool that your organization or you have to negotiate payments, and the higher your patient experience score is, the more you get paid to do what you do.

While the implementation of shared decision making could potentially be seen as a factor that may slow down the flow of patients in a certain day, providing patients with educational material that they can go over at home could actually shorten the visits and make these visits more productive for both the physician and his now informed patient. In conclusion, you now are as good as your patient’s health education is, and if

you can figure out how to do it right in the new world of patient-centric medicine, you could make more money by working less! —Ibrahim Eid, MD Dr. Eid, a vascular surgeon from Fall River, Mass., is founder and chief of the Center for Vascular Diseases in PrimaCare, a large multispecialty group in Massachusetts and Rhode Island, and founder and chief medical officer of Expert Medical Navigation, a software company that supports shared decision making and patient engagement.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

Effect of Aspirin, NSAIDs on Colorectal Cancer Risk May Reflect Genetic Variations

onsteroidal anti-inflammatory drugs (NSAIDs), particularly aspirin, were associated with an overall lower risk for colorectal cancer (CRC), although this association differed according to certain genetic variations of patients, a recent study has found. Andrew T. Chan, MD, MPH, of Massachusetts General Hospital, in Boston,

Li Hsu, PhD, of the Fred Hutchinson Cancer Research Center, in Seattle, and their colleagues conducted a genomewide analysis of gene by environment interactions between regular use of aspirin, NSAIDs, or both and single nucleotide polymorphisms (SNPs; genetic variations) in relation to the risk for developing CRC.

The researchers used data from five case–control and five cohort studies initiated between 1976 and 2003 across the United States, Canada, Australia and Germany and included patients (n=8,634) with CRC and matched controls (n=8,553) between 1976 and 2011. Participants were all of European descent. An analysis of the overall data

indicated that regular use of aspirin and/ or NSAIDs was associated with lower risk for CRC compared with nonregular use (prevalence, 28% vs. 38%; P=6.2 P ×1028 ; JAMA A 2015;313:1133-1142). But among individuals with two fewer common genotypes of rs169732255 (AC or CC, 9% of participants; P P=0.76), no see Aspirin, page 60

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

For GERD-Free Sleep, Inclining Is Plain PHILADELPHIA—Patients with nighttime reflux have long been advised to sleep with their heads elevated, and studies have shown that sleeping on the left side reduces reflux. New research on a two-piece ramp-like device that elevates the body by 20 degrees suggests it helps patients maintain an ideal sleep position and significantly reduces the symptoms of nocturnal gastroesophageal reflux disease (GERD). “A lot of people who use these prop-up

devices to deal with GERD have issues with them,” said Sanath Allampati, MD, a physician researcher with the Digestive Disease Institute at Cleveland Clinic, in Ohio. “They start out with their head higher, but scoot down overnight. We were hoping to find a device that would obviate that. With this one, once patients find a comfortable position, they feel a whole lot better.” In 2013, researchers presented data at the American College of Gastroenterology’s (ACG) annual meeting showing that

volunteers who, after eating a McDonald’s meal, slept on their left side using their sleep-assist device had reduced acid levels in the morning (abstract 27). “That showed it worked, but the study population didn’t have reflux, so we tested it with people who complained of heartburn and regurgitation at night to see if it really helped improve symptoms,” said Scott Gabbard, MD, of Cleveland Clinic’s Digestive Disease Institute. The pilot study, presented as a poster

at the 2014 annual meeting of the ACG (abstract P613), included nine patients taking proton pump inhibitors but still experiencing frequent moderate to severe nocturnal GERD symptoms; five patients were on twice-daily medication.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

Upon enrollment, patients completed the Nocturnal GERD Symptom Severity and Impact Questionnaire (N-GSSIQ). All received a Medcline system, which consists of an incline base and a lateral body pillow, and were instructed to sleep on their left side for at least six hours per night for six weeks. The researchers then repeated the survey. Of the eight patients who completed the study, all reported significant improvements in N-GSSIQ scores. Total scores fell from a mean of 54.3 to 15.4 (P<0.001); nocturnal GERD fell from a mean of 35.1

to 8.1 (P<0.001); and concern about nocturnal GERD fell from a mean of 14.3 to 5.6 (P=0.002). P “The results were outstanding,” Dr. Gabbard said. “They improved not only nocturnal GERD symptoms, but how well they slept, how irritable they were in the morning and concern that the nocturnal GERD will get worse at night and that it could cause permanent damage.” David Johnson, MD, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School, in Norfolk, said the sleep system might indeed help

patients with nocturnal GERD, particularly those who experience regurgitation. “The [findings] need to be better defined, but the science is thought-provoking and suggests that in this subset of patient this [sleep device] has a benefit,” Dr. Johnson told Gastroenterology & Endoscopy News. Dr. Johnson generally advises patients to purchase foam wedges from a home goods store to achieve elevation, “but those don’t give patients support in the left lateral position. We know that patients report less reflux when they start out on their left side, and this locks them into place. But it

Free Colonoscopies Save System Money NYC hospital finds no-cost screening avoids costly cancers New York—Cost is recognized as one of the barriers to screening colonoscopy, the uptake of which hovers at around 65% of the eligible population in the United States. Although it may seem counterintuitive in today’s cost-conscious medical landscape, offering screening colonoscopy free of charge may be a feasible way around this obstacle.

would be good to know how tolerable they found it; I would include a sleep quality assessment in a study like this.” Dr. Gabbard and his colleagues are conducting a larger trial and expect to report the findings at Digestive Disease Week 2015. Amenity Health, which donated the devices used in the study, is working with insurance providers to establish reimbursement for Medcline, and coverage is expected in early 2015. The company declined to discuss the current price of the product. —Monica J. Smith

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

To Treat or Not To Treat CMV: A Critical Question for Colitis Patients New data paint virus as more than an innocent bystander

reating cytomegalovirus infection in patients who have ulcerative colitis may stave off colectomy, new research suggests. “We should strongly consider treating these patients,” said Yinghong Wang, MD, PhD, a gastroenterologist at the Cleveland Clinic, in Ohio, and the lead author of the new study. “Hopefully, it

will at least delay colectomy, if not avoid it completely.” Dr. Wang presented the results at the 2014 Advances in Inflammatory Bowel Diseases (AIBD) annual conference, in Orlando, Fla. (abstract P-30). Cytomegalovirus (CMV) is among the most common of the opportunistic infections faced by patients with inflammatory

bowel disease (IBD), and is often associated with exacerbated symptoms of the intestinal condition. Overall, CMV colitis affects as many as about one-third of patients with steroid-refractory IBD. Dr. Wang noted, however, that research has involved small numbers of patients and has left open a critical question for clinicians: Is CMV behind the exacerbation,

and therefore critical to treat, or is the infection merely an innocent bystander that can be ignored? “We’ve recognized this problem for almost 20 years now,” she said. “It’s always a dilemma.” The usual treatment for CMV is one week of IV gancyclovir 5 mg/kg, then three weeks of oral valcytes 900 mg taken twice daily, Dr. Wang said. The historical cohort study included 40

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

ulcerative colitis (UC) patients identified in the Cleveland Clinic’s clinical pathology database with positive immunohistochemistry for CMV on colon biopsy from 1990 to 2013. Among these patients, 25 (62.5%) received CMV treatment. Patients with positive blood CMV DNA, defined as more than 1,000 copies in whole blood, received antiviral treatment more often than those with levels less than 1,000 copies (44% vs. 13.3%; P<0.01). The researchers found that CMV treatment for patients with UC led to lower rates of colectomy within both

30 days (28% vs. 66.7%; P<0.01) and one year (52% vs. 73.3%; P<0.01). They reported no significant differences between treatment groups for other outcomes: hospitalization, rehospitalization and mortality within 12 months. Clinical outcomes for treated patients also did not differ based on the presence or absence of CMV DNA in blood.

‘Very Good Signal’ Dr. Wang said the findings are a “very good signal” for the treatment of UC in patients who have a positive tissue biopsy.

She also noted that this was a different signal from the one she had previously gleaned from an inpatient database for both Crohn’s disease and UC patients. At the 2013 annual meeting of the American College of Gastroenterology, Dr. Wang presented results from that database, which suggested CMV treatment had minimal effect on outcomes for Crohn’s disease and UC inpatients (abstract 27). This year, with a larger database of both inpatients and outpatients, her team was able to tease out significant treatment

benefits specifically for patients with UC. It appears that treatment in Crohn’s disease patients may not be so critical, Dr. Wang said, although more data are needed for a definitive study. Ellen Scherl, MD, director of the Jill Roberts Center for Inflammatory Bowel Disease at Weill Cornell Medical College, in New York City, called the new findings an “important reminder.” “Underlying CMV is a common and overlooked reason for failure to respond to therapy,” Dr. Scherl said. “The stakes are very high in ulcerative colitis.” However, Gary Lichtenstein, MD, director of the IBD program at the Hospital of the University of Pennsylvania, in Philadelphia, cautioned against inferring too much from the study. He highlighted limitations, including the selection bias inherent in retrospective studies and the fact that techniques for CMV detection have changed substantially between 1990 and 2013. “It’s an interesting finding,” Dr. Lichtenstein added, “and it deserves to be studied further.” —Lynne Peeples Drs. Wang, Scherl and Lichtenstein reported no relevant financial conflicts of interest. Drs. Scherl and Lichtenstein are members of the editorial board of Gastroenterology & Endoscopy News.

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

Preventing Hospital-Acquired Clostridium difficile Infections Brian Currie, MD, MPH Vice President, Medical Research Division of Infectious Diseases Montefiore Medical Center Assistant Dean for Clinical Research Professor of Clinical Medicine Albert Einstein College of Medicine New York, New York

he past 20 years have seen a dramatic change in the epidemiology of Clostridium difficile infections (CDI) in the United States and on a global basis. The frequency of infections has dramatically increased—from 2000 to 2009 the number of US hospitalized patients with any CDI discharge diagnosis more than doubled, from approximately 139,000 to 336,600 and the number with a primary CDI diagnosis more than tripled, from 33,000 to 111,000. Overall incidence of infections has increased dramatically over the period from 2001 to 2012 (Table 1).1-3 Data from the Centers for Disease Control and Prevention (CDC) National Health Safety Network have identified a 28% increase in the number of reported acute care–onset CDI cases from 2010 to 2012.4 Simultaneously, there has been a significant trend toward increased severity of infections during the epidemic, which has been largely attributed to the emergence and rapid dissemination of a virulent strain of C. difficile—the e NAP1/BI/027 strain. CDI-related deaths increased 400% from 2000 to 2007, and CDI now accounts for at least 14,000 patient deaths annually.5,6 Beyond the increased morbidity and mortality, CDIs are estimated to cost US acute care hospitals $800 million per year.7 CDIs now account for 12.1% of all hospitalacquired infections and C. difficilee has become the most common nosocomial pathogen.8 Guidelines for controlling CDI prevalence in acute care settings were issued early in the epidemic and have been updated over the years. Although every acute care hospital in the United States has adopted and initiated some components of these recommendations, it is clear that the CDI epidemic continues unabated and that it has been refractory to the control efforts that have been put in place to date. This review revisits potential CDI control interventions for acute care hospitals, including the existing evidence for their effectiveness. It focuses on primary CDI prevention activities.

could prevent the transmission of C. difficilee and reduce primary CDI rates. Guidelines from the Association for Professionals in Infection Control and Epidemiologg y (APIC), Society for Healthcare Epidemiology (SHE EA)/Infectious Diseases Society of America (IDSA), and CDC have all recommended a series of infection n control and environmental hygiene CDI control inteerventions for many years (Table 2).9-12 The CDC guideelines and the most recent SHEA/IDSA guidelines haave recommended a tiered approach to the initiation off interventions until effective CDI control is achieved. There is currently no data on how individual hospitals haave chosen which of these components to adopt and impllement or how many of the options they have instituted, nor how, or if, they have adopted the recommendationss to document compliance with the measures. As hospiitals initiated infection control and environmental hyggiene interventions, investigations began to documentt an “accumulating impact” of successively introduced prevention measures in reducing CDI rates. This concep ptually resulted in a “bundled” approach to the initiatioon of infection control—the simultaneous initiation off key infection control and environmental hygiene interventions.13,14 Three reports in the literaturee demonstrate that the hospital-wide introduction of CDI-bundled

Table 1. Acute Care Hospitalizations With CDI Discharge Diagnosis2,3 Year

Annual Rate/100 Hospitalizations

2001

5.6

2008

11.6

2009

11.3

2010

11.5

2011

12.4

2012

13.6

CDI,, Clostridium difficile infection

Table 2. Recommended Infection Control/Environmental Hygiene Measures for CDI Prevention9-12 Infection Control •

Infection Control and Environmental Hygiene

•

It is well established that the primary mode of C. difficilee transmission within hospital facilities is person-to-person spread by ingestion of spores shed by symptomatic infected patients. The process is mediated by transient colonization of health care workers’ hands with spores and from contact with environmental reservoirs of spores. C. difficilee spores are extremely hardy and can survive in the inanimate environment for weeks. Additionally, evidence has accumulated that C. difficilee spores are resistant to alcohol-based hand products and most commonly used hospital disinfectants. This has resulted in recommendation of the use of soap and water for hand hygiene and diluted bleach for environmental disinfection in C. difficilee control efforts. The existing evidence strongly suggests that targeted infection control and environmental hygiene interventions

• • • • • •

Rapid testing of symptomatic patients or empiric contact isolation until testing completed Contact isolation Room signage Single room with private toilet or commode Dedicated equipment Gloves and gowns when entering room Hand hygiene with soap and water when entering and leaving room Monitor compliance with hand hygiene and isolation protocols

Environmental Hygiene •

Cleaning and disinfection of equipment, high-touch surfaces, and floor

• •

Use bleach-based disinfectant Monitor compliance/effectiveness with checklist

CDI, Clostridium difficile infection

interventions substantially reduced institutional CDI rates.15-17 In Salgado et al, bundle interventions included staff education, empiric placement of all patients with diarrhea into contact isolation, environmental disinfection with a bleach product, and soap and water for hand hygiene.15 Implementation was associated with a 45.3% decrease in the institutional CDI rate, which was sustained over a subsequent 3-year period. Abbett et al used a bundle consisting of staff education, soap and water hand hygiene, environmental disinfection with bleach bleach, and enhanced communication strategies between caregivers, laboratory staff, and environmental services personnel to promote earlier diagnostic testing, earlier initiation of isolation precautions, and treatment. These interventions were superimposed on already existing policies regarding use of contact isolation. The bundle intervention was associated with a 40% reduction in the institutional CDI rate.16 Finally, Muto et al employed a bundle consisting of staff education, increased and earlier case finding, soap and water hand hygiene, bleach for environmental disinfection, development of a C. difficilee management team, monitored compliance with hand hygiene and isolation protocols, and an antimicrobial stewardship program (ASP) targeting antibiotics considered high risk for CDI. Bundle initiation was associated with a reduction in the institutional CDI rate from 10.4 cases to 2 to 4 cases per 1,000 discharges.17 Koll et al described a 35-hospital study designed to evaluate the impact of instituting an infection control/ environmental services intervention bundle on primary CDI rates.18 Each participating hospital was required to develop an internal interdisciplinary team consisting of infection preventionists, physician and nursing champions, environmental support staff, and quality improvement personnel to drive the bundle intervention. A prebundle evaluation documented significant variability in CDI-directed infection control and environmental services interventions in place among hospitals, and only 52% measured compliance with adopted prevention practices. A standardized bundle was created including rapid initiation of contact isolation of all patients with diarrhea, soap and water hand hygiene with monitored compliance, standardized bleach-based environmental disinfection with a checklist, and patient-dedicated rectal thermometers. Contact isolation included use of single rooms and use of glove and gown personal protective equipment. Standardized CDI case definitions and case finding methodologies were also instituted. see C. difficile, page 18

Q&A: Fecal Lactoferrin Testing ADVERTORIAL

Q: What is Lactoferrin? A: Lactoferrin is a protein found in activated neutrophils (fecal leukocytes). When there is inflammation in the intestines, activated neutrophils will be shed into the stool. Thus, an elevated level of fecal lactoferrin indicates intestinal inflammation.

Q: What causes intestinal inflammation? A: Intestinal inflammation is caused by many different conditions. Two diseases are especially associated with inflammation. Inflammatory Bowel Disease (IBD) is the primary cause of noninfectious intestinal inflammation and can be difficult to distinguish from other intestinal disorders, especially Irritable Bowel Syndrome (IBS). Clostridium difficilee disease, also referred to as C. difficilee infection (CDI), is the primary cause of infectious intestinal inflammation. Q: What is the role of fecal lactoferrin in diagnosing and managing intestinal inflammation? A: A positive test result for elevated fecal lactoferrin in persons who have tested negative for infectious etiologies should alert the physician to possible IBD. A negative result may signal a functional disorder like IBS, which is non-inflammatory. Levels of fecal lactoferrin correlate with disease activity and may be used as an indicator of mucosal healing. C. difficilee disease is complicated to diagnose because the presence of the organism does not always correlate with disease. In many instances, persons who are infected with C. difficilee are simply carriers of the organism and do not need to be treated for CDI. Elevated fecal lactoferrin in persons who are positive for C. difficilee and its toxins help identify the disease, and can indicate if the intestines have become inflamed. In both diseases, whether found separately or together (as is often the case), lactoferrin testing aids in determining disease severity and appropriate therapy.

Q: How does lactoferrin testing compare with other technologies? A: Lactoferrin is more stable in feces, exceeding all other FDAcleared fecal biomarker assays.

Fecal lactoferrin can be accurately measured in specimens with levels remaining unchanged for up to 2 weeks when samples are stored at room temperature or in the refrigerator. This translates into

more reliable testing for intestinal inflammation.

Q: Are these tests reimbursable? A: Yes, lactoferrin testing is covered by most health insurance plans.

A simple stool sample can speak volumes on intestinal inflammation

Get a reliable first read on intestinal inflammation with

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

C. difficile continued from page 16

Bundle initiation was associated with a 33% decline in CDI rate, and the largest decreases were observed for hospitals that started the initiative with more elevated CDI rates.18 Existing evidence suggests that carefully designed and systematically implemented infection control/ environmental hygiene intervention bundles targeting CDI prevention can substantially reduce CDI rates in acute care hospitals. Furthermore, studies have demonstrated that these interventions can be successfully implemented across large numbers of hospitals and that they will have maximal impact in institutions that have the highest CDI rates.

Antimicrobial Stewardship And Primary Prevention Given that the great majority of patients with CDI have had prior exposure to antimicrobial agents, it is almost intuitive to consider limitation or restriction of antibiotics associated with the development of CDI as a primary preventive measure. Current APIC, SHEA/ IDSA, and CDC guidelines recommend implementation of institution-wide ASPs as a measure to affect primary CDI rates, and the practice has been widely supported in the literature, although there have only been limited data regarding the efficacy of this approach and limited guidance as to how to accomplish desired outcomes. Nearly all antibiotics have been associated with the onset of CDI, and a single dose of preoperative antibiotic has been demonstrated to be sufficient to cause infection.9,19 There are numerous investigations in the literature attempting to identify the CDI risk associated with specific antibiotics, but the widespread use of antimicrobial agents and polypharmacy have complicated the process of identifying them. Clindamycin and cephalosporin antibiotic therapy consistently has been identified with increased risk for CDI.9 Fluoroquinolone antibiotics have been suggested to carry increased risk for CDI infection based on the fact that the NAP1/BI/027 strain exhibits high-level fluoroquinolone resistance, but the evidence to support this association remains controversial.9 There are a number of reports in which antibiotic stewardship activities alone, or in conjunction with other infection control and environmental interventions, have been able to reduce primary CDI rates. Successful clindamycin restriction has been demonstrated to significantly reduce CDI rates in 2 studies.20,21 Two other studies were able to document significant reductions in CDI rates with reductions in broad-spectrum antibiotic prescribing (defined as second- and third-generation cephalosporins, piperacillin/tazobactam, carbapenems, fluoroquinolones, and

vancomycin) and by targeting imipenem and piperacillin prescribing.22,23 Both of these studies used a prospective audit and feedback approach and activities were ICUspecific. Three additional hospital-wide intervention studies targeted CDI high-risk antibiotics (defined as second- and third-generation cephalosporins, fluoroquinolones, and clindamycin), third-generation cephalosporin and aztreonam antibiotic prescribing, and cephalosporins and amoxicillin clavulanate.24-26 All studies were able to significantly reduce targeted antibiotic prescription and primary CDI rates. A recent multicenter “before-and-after” intervention comparative study sought to identify the potential additive contribution of C. difficile–targeted e antimicrobial stewardship activities in preventing primary CDI among 6 intervention and 4 control hospitals that had already documented more than 80% compliance with a prior CDI infection control/environmental services prevention bundle.27 State CDI reporting was mandatory for all participating hospitals, ensuring uniform case definitions and case finding methodologies. A case–control study approach was developed to allow each intervention institution to identify which antibiotics appeared to be high risk for CDI.28 Statistically significant odds ratios and evaluation of prescription frequency identified piperacillin/tazobactam as a targeted antibiotic at all 6 hospitals, quinolone antibiotics at 3 hospitals, and cefepime at 2 hospitals. Each hospital developed its own hospitalwide intervention program, including components of audit and feedback, antibiotic restriction, institution of treatment algorithms, and physician education. Modest reductions in targeted antibiotics were documented and, although there was a trend toward a reduced CDI rate among intervention hospitals compared with controls, the difference was not statistically significant. Participating ASP staff noted that the development of successful interventions was a slow process and that the full impact of interventions may not have been captured in the 1-year study period. They also emphasized that the large volume of targeted antibiotic prescriptions presented a challenge that may have exceeded available resources for the task.28 Clearly, there is a continued need to identify the most effective ways to study, measure, and operationalize ASPs as a potential component of multipronged hospital CDI control activities.

Probiotics for Primary Prevention of CDI? Probiotic administration for the prevention of primary CDI is a controversial topic. Although the practice has been advocated for many years, there are only a few studies that demonstrate efficacy.9 Adjunctive therapy with probiotics has been used widely for patients, with or without the guidance of physicians, and a recent study investigating probiotic prescriptions at an academic

medical center found that the documented indication for 72% of the prescriptions was either antibiotic-associated diarrhea, primary CDI prevention, or CDI treatment.28 The use of probiotic therapy for primary CDI prevention is intended to mitigate the effects of antibiotic disruption of bowel microbiota, and different mechanisms have been proposed to explain how specific probiotics can affect the microbiota and interfere with C. difficile.30 Most studies of CDI prevention have focused on secondary prevention (prevention of CDI recurrence) because the risk for recurrent infection (20%-30%) is much higher than primary CDI (<10%) and smaller sample sizes are required for investigation. Historically, there are only limited studies investigating probiotics for primary prevention of CDI, and they have been poorly designed and underpowered because of small sample sizes. Several recent reports, including 2 meta-analysis studies and a quasi-experimental prospective cohort study investigating the impact of adding probiotics to an already existing CDI prevention bundle, have suggested that probiotics may have some utility for primary prevention of CDI, but they are far from conclusive.30-32 The large number of probiotic agents and the numerous combination preparations available are an obstacle to performing any type of definitive meta-analysis, and meta-analysis investigations often include studies investigating both primary and secondary prevention. Finally, the FDA regulates probiotics as food supplements, not as pharmaceuticals; as such, there is lack of standardization of the available probiotic products regarding dosage, potency, shelf life, and purity.9 Manufacturing standards may even vary between commercial preparations of the same species of probiotic, and these variations have been demonstrated to influence the properties of the final products.33 Although APIC and CDC practice guidelines do not address the use of probiotics, the 2010 SHEA/ IDSA update of the clinical practice guidelines for CDI addressed the issue and specifically did not recommend the administration of probiotics for primary CDI prevention, noting that there were limited data to support the practice and that there was a potential downside given the risk for acquiring a probiotic-related infection.9 Further research studies using well-designed, randomized, placebo-controlled clinical trials to investigate the potential of individual probiotic agents for primary CDI prevention are required, and until they are completed probiotic primary CDI prevention will remain controversial.

Vaccines and Biologics There are currently 3 toxoid-based C. difficilee vaccines in development (Table 3).34,35 Two of them, Sanofi-Pasteur’s ACAM-CDIFF and Pfizer’s PF-06425090, are in clinical trials for evaluation as primary CDI prevention

Table 3. Vaccines and Biologic Agents in Development for Primary Prophylaxis of CDI34-38 Product

Antigen

Delivery

Clinical Trial Status

ACAM-CDIFF (Sanofi-Pasteur)

Formalin-inactivated toxins A and B

IM injections days 0, 7, and 28-30

Phase III for primary prevention

PF-06425090 (Pfizer)

Molecular and chemically inactivated toxins A and B

3 IM injections

Phase II for primary prevention; FDA fast-track status

IC84 (Valneva)

Recombinant fusion protein of toxin A and B binding regions

IM injection days 0, 7, and 21

Completion of Phase I safety and immune response

Oral suspension

Phase II for recurrent CDI

Vaccines

Biologics VP20621 (ViroPharma) Spores of nontoxogenic Clostridium difficile strain M3 CDI, Clostridium difficile difficile infection; infectio on; IM, intramuscular

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

agents. A third, IC84 (Valneva), is included in this discussion, although only Phase I safety and immune response studies have been completed. Although they are all toxoid-based vaccines designed to elicit antibodies directed at both C. difficilee toxins A and B, they differ in the nature of the presented antigen. ACAMCDIFF uses a formalin-inactivated preparation of toxins A and B; PF-06425090 uses recombinant toxin A and B mutants that are chemically inactivated; and IC84 is based on the use of a recombinant fusion protein containing toxin A and B binding regions. All 3 are preparations for intramuscular injection; all have been shown to be safe and well tolerated; and all have been demonstrated to be immunogenic in healthy adults after 3 serial injections over a 3- to 4-week period. IC84 also has been demonstrated to be highly immunogenic in older patients. The Phase III trial of ACAM-CDIFF vaccine is projected to be completed by the end of 2015. A single biologic agent, VP20621 (ViroPharma), is currently being developed as a biotherapeutic agent and is in Phase II studies for evaluation for use in treating recurrent CDI.34,36,37 VP20621 consists of an oral suspension of the spores of the non-toxogenic C. difficile strain M3, which had been previously shown to be protective against challenge with toxogenic strains in hamsters. Completed Phase I trials have demonstrated safety and tolerability (no diarrhea or change in bowel habits) to either single or multiple doses, and persistent colonization with VP20261 was detected in 44% of study participants at 21 to 28 days.38 To date, the actual mechanism of CDI protection accorded by VP20261 remains obscure.36 Should these agents become available in the near future, further research will be required to determine if they can be implemented in a cost-effective manner and to determine the extent to which they can contribute to reducing the total burden of primary CDI among hospitalized patients.

Conclusion The acute care hospital CDI epidemic has been refractory to hospital-directed control efforts to date. These activities need to be revisited and optimized to provide maximal impact on this continuing urgent public health threat. There is existing evidence that a bundled infection control/environmental hygiene intervention can significantly reduce acute care hospital primary CDI rates, with maximal impact evident in hospitals with more elevated CDI rates. Furthermore, there is now an existing validated footprint for these activities that describes an intervention that has been successfully introduced across a fairly diverse group of hospitals. Implementation of this type of bundle is challenging. The transmission of C. difficilee in the acute care setting is a complex process and, thus, designed interventions are complex and multifaceted. They involve a wide variety of health care professionals (physicians, nurses, infection control practitioners, and environmental services staff ), who must all take ownership of the problem and coordinate their efforts to achieve successful outcomes. It is noteworthy that successful programs documented in this review often included the formation of an interdisciplinary team as a key component to drive the interventions on an institutional level. They also have all incorporated programs to measure compliance, and were able to document that they had achieved exceptionally high levels of compliance with the infection control components by direct observation and with the environmental hygiene

components by the use of checklists. The evidence presented in this report suggests that many hospitals are not measuring compliance with the CDI control programs that they have initiated to date. Measuring compliance is labor-intensive, but iterative staff feedback about performance is required to change existing behavioral patterns. A team approach brings greater resources to the task, but the long-term sustainability of this type of intervention beyond a 2-year period remains to be established. Public health officials and regulatory bodies need to identify a way to motivate hospitals to take on the infection control/environmental hygiene bundle and to provide explicit guidance, direction, and encouragement to maximize success and sustain the activity. There is less firm evidence regarding the efficacy of ASPs designed to reduce CDI rates. It is clear that these types of activities will require both access to institutional pharmacy prescribing databases and an individual tailored risk assessment to identify high-risk antibiotics that should be targeted at each institution. Changing complex and established prescription behavioral patterns is a slow process, and it is worth noting that reports of ASPs that have successfully reduced CDI rates usually document a cumulative effect that increases over a number of years. In large hospitals, the volume of targeted antibiotic use may overwhelm the ASP team. However, there is some evidence suggesting that ASPs can be used in a more limited way, such as targeting single hospital units that have a concentrated CDI burden. Future research will need to continue to refine this type of intervention and clearly document efficacy. Furthermore, even if found efficacious, it is not clear how widely these programs can be established across all US hospitals, given the financial and professional resources required to establish an ASP. Probiotic use remains controversial, and definitive studies are still required to establish that they can reduce CDIs. Finally, although all aspects of the host–pathogen relationship have not been clearly ascertained for C. difficile, there are 3 promising vaccines and a biologic in active development and clinical trials for CDI prevention.

References 1. McDonald LC, Lessa F, Sievert D, et al. MMWR. 2012;61(9):157-162. 2. Steiner C, Barrett M, Terrel L. HCUP projections: Clostridium difficilee hospitalizations 2011 to 2012. 2012. HCUP Projection Report #2012-01. US. Agency for Healthcare Research and Quality. http://www.hcup-us. ahrq.gov/reports/projections/2012-01.pdf. Accessed January 15, 2015. 3. Department of Health and Human Services. National targets and metrics. National action plan to prevent health care-associated infections: road map to elimination; 2013. http://www.health.gov/nai/prevent_hai.asp. Accessed January 15, 2015. 4. Department of Health and Human Services. Progress toward eliminating health care-associated infections meeting summary. http://www.health.gov/hai/pdfs/2012hai-progress-meeting-summary.pdf. Accessed January 15, 2015. 5. Centers for Disease Control and Prevention. Investigating Clostridium difficilee infections across the US emerging infections program—healthcare-associated infections community interface activity. http://www.cdc.gov/hai/pdf/ eip/pdf/Cdiff-factsheet.pdf. Accessed January 15, 2015. 6. Centers for Disease Control and Prevention. CDC vital signs. http://www.cdc.gov/vitalsigns/pdf/2012-03-vitalsigns.pdf. Accessed January 15, 2015.

7. McGlone SM, Bailey RR, Zimmer SM, et al. Clin Microbiol Infect. 2012;18(3):282-289. 8. Magill SS, Edwards JR, Bamberg W, et al. N Engl J Med. 2014;370(13):1198-1208. 9. Cohen SH, Gerding DN, Johnson S, et al. Infect Control Hosp Epidemiol. l 2010;31(5):431-455. 10. Association for Professionals in Infection Control and Epidemiology. Guide to preventing Clostridium difficile infections. APIC Implementation Guide. http://www. apic.org/Resource_/EliminationGuideForm/59397fc63f90-43d1-9325-e8be75d86888/File/2013CDiffFinal. pdf. Accessed January 15, 2015. 11. Siegel JD, Rhinehart E. Jackson M, et al. Centers for Disease Control and Prevention. Management of multidrugresistant organisms in healthcare settings, 2006. http:// www.cdc.gov/hicpac/pdf/guidelines/MDROGuideline2006.pdf. Accessed January 15, 2015. 12. Dubberke ER, Carling P, Carrico R, et al. Infect Control Hosp Epidemiol. 2014;35(6):628-645. 13. McDonald CL. Clin Infect Dis. 2007;45(10):1274-1276. 14. Gerding DN, Johnson S. Clin Infect Dis. 2010;51(11):1306-1313. 15.Salgado CD, Mauldin PD, Fogle PJ, et al. Am J Infect Control. 2009;37(6):458-464. 16.Abbett SK, Yokoe DS, Lipsitz SR, et al. Infect Control Hosp Epidemiol. l 2009;30(11):1062-1069. 17.Muto CA, Blank MK, Marsh JW, et al. Clin Infect Dis. 2007;45(10):1266-1273. 18.Koll BS, Ruiz RE, Calfee DP, et al. J Healthc Qual. l 2014;36(3):35-45. 19.Privitera G, Scepellini P, Ortisi G, et al. Antimicrob Agents Chemother. 1991;35(1):208-210. 20.Climo MW, Isreal DS, Wong ES, et al. Ann Intern Med. 1998;128(12Pt1):989-995. 21.Pear SM, Willamson TH, Bettin KM, et al. Ann Intern Med. 1994;120(4):272-277. 22.Elligsen M, Walker SA, Pinto R, et al. Infect Control Hosp Epidemiol. 2012;33(4):354-361. 23.Diaz-Granadas CA. Am J Infect Control. l 2012;40(6):526-529. 24.Aldeyab MA, Kearney MP, Scott MG, et al. J Antimicrob Chemother. 2012;67(12):2988-2996. 25.Carling P, Fung T, Killion A, et al. Infect Control Hosp Epidemiol. 2003;24(9):699-706. 26.Fowler S, Webber A, Copper BS, et al. J Antimicrobial Chemother. 2007;59(5):990-995. 27.Ostrowsky B, Ruiz R, Brown S, et al. Infect Control Hosp Epidemiol. l 2014;35(suppl3):S86-S95. 28.Chung P, Currie B, Guo Y, et al. Am J Infect Control. 2014;42(10 suppl):S264-S268. 29.Simkins J, Kaltsas A, Currie B. Int J Infect Dis. 2013;17(5):e321-e324. 30.Johnson S, Mazaide P, McFarland L, et al. Int J Infect Dis. 2012;16(11):786-792. 31.Goldenberg JZ, Ma SS, Saxton JD, et al. Cochrane Database Syst Rev. 2013;5:CD006095. 32.Mazaide PJ, Andriessen JA, Pereira P, et al. Curr Med Res Opin. 2013;29(10):1341-1347. 33.Grzeskowiak L, Isolauri E, Salminen S, et al. Br J Nutr. 2011;105(6):887-894. 34.Gerding DN. Discov Med. 2012;13(68):75-83. 35.Donald RG, Flint M, Kalyan N, et al. Microbiology. 2013;159(7):1254-1266. 36.Gerding DN, Muto CA, Owens RC. Measures to control and prevent Clostridium difficilee infection. Clin Infect Dis. 2008;46(suppl 1):S43-S49. 37.Merrigan MM, Sambol SP, Johnson S, et al. Int J Antimicrob Agents. 2009;33(suppl 1):S46-S50. 38.Villano SA, Seiberling M, Tatarowicz W, et al. Antimicrob Agents Chemother. 2012;56(10):5224-5229.

THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Driving Patient Safety With Endoscopic Tattooing Faculty Douglas K. Rex, MD, MACP, MACG, FASGE, AGAF Distinguished Professor of Medicine Indiana University School of Medicine Chancellor’s Professor Indiana University Purdue University Indianapolis Director of Endoscopy Indiana University Hospital Indianapolis, Indiana

Introduction The 1999 Institute of Medicine report found that preventable medical errors, including wrong-site surgery, caused 44,000 to 98,000 deaths each year, with an associated annual cost of $17 billion to $29 billion.1-3 Even using the conservative estimate, this placed medical errors among the leading causes of death in the United States. Fortunately, safeguards instituted over the past decade have resulted in the reduction of preventable medical errors. This article will discuss the issue of wrong-site surgery in patients with gastrointestinal (GI) disease and the role of endoscopic tattooing in reducing this devastating error in care.

Wrong-Site Surgery in Patients With Endoscopically Defined GI Disease Wrong-site surgery encompasses surgery performed on the wrong side of the body, wrong surgical site, wrong surgical procedure performed, and surgery performed on the wrong patient.4 Wrong-site surgery is also defined as a sentinel event (ie, an unexpected occurrence involving death or serious physical or psychological injuries, or the risk thereof ) by the Joint Commission, which found wrong-site surgeries to be the third highest-ranking event among sentinel events.5 The issue of wrong-site surgery is particularly relevant to GI lesions that are identified endoscopically with subsequent referral for surgery. Indeed, the intraoperative identification of lesions previously detected by endoscopy often is difficult, particularly during laparoscopic surgery.6 Estimation of the tumor site at colonoscopy can be imprecise, with as many as 14% of tumor locations incorrectly identified.7 The lack of accurate lesion identification during laparoscopy may lead to resection of the wrong bowel segment.8 Wrong-site surgery is generally caused by a lack of a formal system to verify the surgical site or a breakdown of the system that verifies the correct site. The Joint Commission Center for Transforming Healthcare estimates that approximately 80% of serious medical errors, including wrong-site surgery, involve miscommunication

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

Figure 1. A 3-quadrant tattoo marking for surgery at the distal end of involvement in a patient with severe serrated polyposis. Image courtesy of Douglas Rex, MD, MACP, MACG, FASGE, AGAF.

Supported by

Clinical Perspective In my practice, endoscopic tattooing is an important clinical tool. Ensuring resection of the correct segment is a joint responsibility between endoscopist and surgeon. It is important to practice appropriate techniques for tattooing; if possible, avoid injecting through the colon into the peritoneal cavity, the omentum, or another organ. The key to success is to approach the mucosa tangentially and not en face. Using a 23- or 25-gauge needle with a 3- to 5-mm tip, I will insert the needle into the wall and then withdraw until only one-third to half of the needle is embedded (Figure 2). Then lift toward the lumen so that the shape of the embedded needle and the location of the needle tip is visible through the mucosa. Make a small injection to confirm a submucosal bleb, and then follow with a large volume (Figure 3). When marking a polyp for subsequent endoscopic resection, the tattoo should not be placed under the lesion. Rather, the tattoo should be placed several centimeters distal to the lesion or on the opposite wall and note the location relative to the lesion in the report. When marking an endoscopic mucosal resection site for easy location at follow-up, I will place the tattoo next to the site and into the remaining submucosal injection mound, and note the location in the report (eg, “with the lesion down the tattoo is to the left”). When marking for surgery, the full circumference of the bowel should be marked. The location of the tattoo (eg, “a circumferential tattoo is placed 3 cm distal to the cancer”) should be

Colon

Lateral spreading tumor

Mucosa Submucosa Muscle layers Serosa

Spot™ inje ection site Positioning recommendation for needle

3 cm distal from tumor

Tattoo placement acement relative to a lateral spreading tumor being marked for later endoscopic resection

Figure 2. Positioning recommendations for injection needle and tattoo placement relative to a lateral spreading tumor. Image courtesy of Douglas Rex, MD, MACP, MACG, FASGE, AGAF.

noted. The endoscopist should be cautious about naming a segment with nonspecific endoscopic landmarks (eg, “the tumor is in the descending colon”).

Conclusion Endoscopic tattoos are a safe and effective method for aiding in the localization of lesions throughout the GI tract and the pancreas. Endoscopists should be prepared to inject a permanent surgical marker during the initial endoscopy or colonoscopy if a lesion cannot be removed; or if an endoscopically removed polyp has clinical features that may require surgical resection or surveillance colonoscopy. Properly performed and documented endoscopic tattooing may prevent wrong-site surgery and is the standard of care to convey definitive disease localization information between the endoscopist and the surgeon.

References 1.

Institute of Medicine. http://www.iom.edu/Reports/1999/ To-Err-is-Human-Building-A-Safer-Health-System.aspx. Accessed April 15, 2015. Kohn LT, Corrigan JM, Donaldson MS. To Err Is Human: Building a Safer Health System. A Report of the Committee on Quality of Health Care in America, Institute of Medicine. Washington, DC: National Academies Press; 2000.

Figure 3. Single tattoo mound placed to the left of an endoscopic mucosal resection site after site closure with clips. Image courtesy of Douglas Rex, MD, MACP, MACG, FASGE, AGAF.

11. Kethu SR, Banerjee S, et al; ASGE Technology Committee. Gastrointest Endosc. 2010;72(4):681-685. 12. Askin MP, Waye JD, Fiedler L, et al. Gastrointest Endosc. 2002;56(3):339-342. 13. McArthur CS, Roayaie S, Waye JD. Surg Endosc. 1999;13(4): 397-400. 14. Nizam R, Siddiqi N, Landas SK, et al. Am J Gastroenterol. 1996;91(19):1804-1808.

Thomas EJ, Studdert DM, Newhouse JP. http://www.jstor.org/ stable/29772835. Accessed April 15, 2015.

AHRQ PSNet patient safety network. http://psnet.ahrq.gov/ primer.aspx?primerID=18. Accessed April 15, 2015.

Joint Commission. http://www.jointcommission.org/se_ data_event_type_by_year_/. Accessed April 15, 2015.

Luigiano C, Ferrara F, Morace C, et al. Adv Ther. 2012; 29(10):864-873.

Vignati P, Welch JP, Cohen JL. Surg Endosc. 1994;8(9): 1085-1087.

19. Zerey M, Hawver LM, Awad Z, et al. Surg Endosc. 2013;27(1): 1-10.

Wexner SD, Cohen SM, Ulrich A, et al. Dis Colon Rectum. 1995;38(7):723-727.

20. Park JW, Sohn DK, Hong CW, et al. Surg Endosc. 2008;22(2): 501-505.

Joint Commission Center for Transforming Healthcare. http://www.jointcommission.org/assets/1/18/hot_topics_ transitions_of_care.pdf. Accessed April 15, 2015.

10. Joint Commission. http://www.jointcommission.org/ assets/1/18/up_poster.pdf. Accessed April 15, 2015.

15. Moghadamyeghaneh Z, Masoomi H, Mills SD, et al. JSLS. 2014;18(4):e2014.00230. 16. Gonzalez R, Smith DC, Mason E, et al. Dis Colon Rectum. 2006;49(2):197-204. 17. Keller D, Jaffe J, Philip MM, et al. Surg Endosc. 2012;26(11): 3101-3105. 18. Rex DK, Schoenfeld PS, Cohen J, et al. Gastrointest Endosc. 2015;81(1):31-53.

Disclosure: Douglas Rex, MD, MACP, MACG, FASGE, AGAF, has received research support from Boston Scientific and Olympus. He has served on scientific advisory boards for American BioOptics, CheckCap, Colonary Solutions, Epigenomics, and Given Imaging. He has received consulting fees from Boston Scientific, Endo-Aid, Ltd., Ironwood Pharmaceuticals, Olympus, and Paion AG. BB155

Similarly, the Society of American Gastrointestinal and Endoscopic Surgeons’ (SAGES) Guidelines for Laparoscopic Resection of Curable Colon and Rectal Cancer state: “When approaching colon resection laparoscopically, every effort should be made to localize the tumor preoperatively. Small lesions should be marked endoscopically with permanent tattoos before surgery to maximize the surgeon’s ability to identify the lesion. Surgeons should be prepared to use colonoscopy intraoperatively if lesion localization is uncertain.”19 Furthermore, these guidelines state: “Tattooing is extremely important for intraoperative localization especially for small tumors or polyps and should be pursued at the time of preoperative colonoscopy. Tattooing should be accomplished using suspended carbon black, commercially prepared for this purpose. Multiple carefully placed intramural injections should be made circumferentially in the colonic wall adjacent to the lesion to maximize the surgeon’s ability to localize the lesion intraoperatively.”19 Transmural injections can result in diffuse intraabdominal staining.20 “If the tumor is not localized preoperatively or the preoperative marking cannot be reliably identified during surgery, intraoperative colonoscopy should be used. When intraoperative colonoscopy is utilized, carbon dioxide insufflation may be preferable as its rapid absorption lessens the risk of a persistently distended colon interfering with surgery.”19

Tent the tissue sue with the needle befo ore injection. Th he needle shap pe visible throu ugh the mucosa verifies submucosall placement

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

continued from page 1

deaths in the United States in this decade alone—and even those deaths are a mere fraction of the total number in which the blood-borne liver disease is implicated, according to the most Michael recent information available to the Houghton, PhD Centers for Disease Control and Prevention (CDC). The CDC estimates that anywhere from 2.7 million to 3.9 million Americans suffer from chronic hepatitis C infection. Globally, the World Health Organization (WHO) puts that number at as many as 150 million, with up to 500,000 deaths worldwide each year. “I think it’s very good news for developing a hep C vaccine,” said Michael Houghton, PhD, the Canada Excellence Research Chair in Virology at the University of Alberta in Edmonton, Manitoba, who led the latest sstudy. “As recently as a few years aago, people were generally thin nking in the field that HCV waas going to be rather like HIV, insofar as being very H difficult to be able to elicit antibodies from a vaccine that could neutralize or kill the infectivity of multiple viral strains.” Dr. Houghton is crediteed with helping discover HCV V, along with collaborators

Normalized Neutralization (%)

Vaccine

Volunteer Number

Figure. Human antisera cross-neutralizes all seven major HCV genotypes. Sera of volunteers 1, 5 and 7 were tested for neutralization activity (representative of two independent experiments performed in triplicate depicted). Source: PLoS ONE. 2013;8:e59776.

Qui-Lim Choo, PhD, and George Kuo, PhD, in 1989, when the three worked together at Chiron Corporation, a California biotech startup (sidebar), in collaboration with Daniel Bradley, PhD, a research scientist at the CDC. A vaccine against hepatitis C could also help curb the demand for direct-acting antiviral agents (DAAs), which can cure the disease, but at a steep cost. DAAs accounted for $4.5 billion in Medicare spending last year—a staggering increase from $286 million in 2013, The Washington Postt reported.

HCV and the Birth of Proteomics f he and his colleagues are successful in developing a vaccine for HCV, the victory will be particularly satisfying for Michael Houghton, PhD. In 1982, five years after earning his doctorate in biochemistry from King’s College London, Dr. Houghton relocated from his native England with his wife and infant son to join the Chiron Corporation, a biotech startup in the San Francisco Bay area. Chiron gave Dr. Houghton his own lab, and together they decided that his lab would focus on a mysterious, frequently deadly viral liver disease known as non-A, non-B hepatitis. Like its relatives, this mysterious infection led to inflammation and loss of function in the liver. Unlike hepatitis A, and most cases of hepatitis B, the illness was chronic. Hepatitis A had been traced to a virus found in feces and transmitted via contaminated food and water, and hepatitis B to a virus transmitted via blood, sex and motherto-baby contact. The disease, which infects up to 150 million people worldwide, would come to be known as hepatitis C—but not for another seven years. “The challenge to non-A, non-B hepatitis was that there was no antibody or any viral antigen, or other

known marker, and relative to hepatitis A and B, it was of much lower infectivity titer,” Dr. Houghton recalled. “So it was a black box. We knew it was there, and we knew it was a serious medical problem, but we had no experimental handle to use.” Together with his Chiron collaborators Qui-Lim Choo, PhD, and George Kuo, PhD, Dr. Houghton went to work on understanding the disease, studying high-quality animal plasma samples, supplied by Daniel Bradley, PhD, at the CDC lab in Atlanta. After several frustrating years spent trying to get an experimental grip on the disease, during which Dr. Houghton estimates the team tried 50 different approaches, they hit upon one so radical, it had never been used before to identify a new virus. “At the time, proteomics wasn’t invented, so we didn’t call it proteomics, but that’s essentially what it was,” Dr. Houghton recalled. “We took animal plasma from Dan Bradley, and we cloned every nucleic acid, whether it was RNA or DNA, into bacteria. And then we were able to persuade the bacteria to express each nucleic acid– cloned nucleic acid into protein. “What you end up with are huge

“Health care systems around the world really cannot afford to give the drugs to everybody,” Dr. Houghton said. “So we need a vaccine to prevent adding to the burden of disease that we currently have.” In sharp contrast to DAAs, which cost a minimum of $50,000 to cure one patient, a vaccine would likely cost around $300, Dr. Houghton said. His lab, along with that of Lorne Tyrell, MD, PhD, at the University of Alberta, in Canada, has received a grant to perform

bacterial libraries,” Dr. Houghton explained. “Each bacteria is expressing a different protein encoded by a different nucleic acid from the animal plasma. Then we mixed serum from patients with non-A, non-B hepatitis with the bacterial library, looking for a specific antigen-antibody reaction. “It was a big risk, since we did not know if this virus produced good antibody titers, since we knew it usually caused chronicity,” he continued. “And also, even under more ideal conditions using known, well-characterized and high-titer antibodies, I knew that this method didn’t always work.” It took two years of immunoproteomic sleuthing for the team to discover what they’d been searching for. After seven years spent screening some 200 million to 300 million clones, they isolated one, then known as clone 5-1-1. A rigorous battery of tests subsequently confirmed clone 5-1-1 to be derived from what is now called the hepatitis C virus. Dr. Houghton takes the contributions of his colleagues as seriously as he takes his own: In 2013, he declined the most prestigious international science prize in Canada, an award from the Gairdner Foundation, because Drs. Choo and Kuo were not named in it. “They were in the scientific

see Vaccine, page 30

‘kitchen and think tank’ right alongside me thinking up and working on new approaches.” Dr. Houghton has been working on a vaccine for HCV ever since the discovery of the virus in 1989. While still at Chiron, he and his colleagues performed clinical trials on a vaccine that was the prototype for the University of Alberta vaccine that will go into clinical trials within two or three years. The initial prototype demonstrated that the vaccine was “safe, well tolerated and good at eliciting T-cell and general antibody responses,” he said. Subsequent studies performed with researchers at the University of Alberta, including one published in 2013 and the present study, demonstrated that the vaccine produces antibodies that are effective at neutralizing the infectivity of multiple genotypes of HCV. One of the factors that makes HCV so difficult to vaccinate against is that there are seven distinct genotypes, comprising hundreds or even thousands of variations of the virus found around the world. Based on the results so far, Dr. Houghton is optimistic that a vaccine derived from two or three of these major genotypes will be effective against all or at least most of the seven major global genotypes. —A.R.

IN THE TREATMENT OF CHRONIC HEPATITIS B (CHB) IN ADULTS WITH COMPENSATED LIVER DISEASE

VIROLOGIC RESPONSE. LONG-TERM RESISTANCE.

TWO REASONS TO CHOOSE VIREAD Complete response achieved at 1 year The primary endpoint in Studies 102 and 103 was complete response to treatment at 48 weeks as defined by HBV DNA <400 copies/mL + histological response (Knodell necroinflammatory score improvement of ≥2 points without worsening in Knodell fibrosis score).1,2

71%

of HBeAg– VIREAD patients vs 49% of adefovir dipivoxil patients1,3

67%

of HBeAg+ VIREAD patients vs 12% of adefovir dipivoxil patients1,4

In Study 102 (HBeAg–, n=375) and Study 103 (HBeAg+, n=266), a combined total of 641 adult patients with CHB and compensated liver disease who were nucleoside treatment naïve entered a 48-week, randomized, double-blind, active-controlled treatment period comparing VIREAD 300 mg to adefovir dipivoxil 10 mg. Subjects who completed double-blind treatment at Week 48 were eligible to roll over with no interruption in treatment to open-label VIREAD. Of 641 patients enrolled in the initial trials, 489 (76%) completed 240 weeks of treatment.1-5

VIREAD should not be administered in combination with adefovir dipivoxil.1

Indication and Usage

Important Safety Information

VIREAD® (tenofovir disoproxil fumarate) is indicated for the treatment of chronic hepatitis B in adults and pediatric patients 12 years of age and older. The following points should be considered when initiating therapy with VIREAD for the treatment of HBV infection: s The indication in adults is based on data from treatment of subjects who were nucleoside–treatment-naïve and treatment-experienced with documented resistance to lamivudine. Subjects were adults with HBeAg-positive and HBeAg-negative chronic hepatitis B with compensated liver disease s VIREAD was evaluated in a limited number of subjects with chronic hepatitis B and decompensated liver disease s The numbers of subjects in clinical trials who had adefovir resistance-associated substitutions at baseline were too small to reach conclusions of efﬁcacy

BOXED WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS

Please see VIREAD Important Safety Information continued and Brief Summary of full Prescribing Information, including BOXED WARNING, on the following pages.

s Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, in combination with other antiretrovirals s Severe acute exacerbations of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including VIREAD. therapy VIREAD Hepatic function should be monitored closely with both clinical and laboratory followup for at least several months in patients who discontinue anti-hepatitis B therapy, including VIREAD. If appropriate, resumption of anti-hepatitis B therapy may be warranted

NO HBV RESISTANCE DEVELOPED THROUGH YEAR 7 Annual evaluation of resistance was a prespeciﬁed secondary endpoint. Cumulative VIREAD genotypic resistance has been evaluated for up to 240 weeks in Studies 102, 103, 106, 108, and 121.1,3,4 s In the nucleotide-naïve population from Studies 102 and 103, HBeAg+ subjects had a higher baseline viral load than HBeAg– subjects and a signiﬁcantly higher proportion of the subjects remained viremic at their last time point on VIREAD monotherapy (15% vs 4%, respectively) Not an actual patient, but is representative of a real patient type. Models are used for illustrative purposes only.

s HBV isolates from these subjects who remained viremic showed treatment-emergent substitutions; however, no speciﬁc substitutions occurred at a sufﬁcient frequency to be associated with resistance to VIREAD (genotypic and phenotypic analyses)

Important Safety Information (cont’d) Warnings and Precautions s New onset or worsening renal impairment: Cases of acute renal failure and Fanconi syndrome have been reported with the use of VIREAD. In all patients, assess estimated creatinine clearance (CrCl) prior to initiating and during therapy. In patients at risk for renal dysfunction, including those who previously experienced renal events while receiving adefovir dipivoxil, additionally monitor serum phosphorus, urine glucose, and urine protein. In patients with CrCl <50 mL/min, adjust dosing interval and closely monitor renal function. Avoid concurrent or recent use with a nephrotoxic agent. Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after initiation of high dose or multiple NSAIDs in HIV-infected patients with risk factors for renal dysfunction; consider alternatives to NSAIDs in these patients. Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function s Coadministration with other products: – Do not use in combination with other products containing tenofovir disoproxil fumarate – Do not administer in combination with adefovir dipivoxil s Patients coinfected with HIV-1 and HBV: Due to the risk of development of HIV-1 resistance, VIREAD should only be used in HIV-1 and HBV coinfected patients as part of an appropriate antiretroviral combination regimen. HIV-1 antibody testing should be offered to all HBV-infected patients before initiating therapy with VIREAD s Bone effects: Decreases in bone mineral density (BMD) and mineralization defects, including osteomalacia, have been seen

in patients treated with VIREAD. Consider assessment of BMD in adult and pediatric patients who have a history of pathologic bone fracture or other risk factors for bone loss. In a clinical trial conducted in pediatric subjects 12 to <18 years of age with chronic hepatitis B, total body BMD gain was less in VIREADtreated subjects as compared to the control group. In patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms, hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered

Adverse Reactions s In HBV-infected subjects with compensated liver disease: Most common adverse reaction (all grades) was nausea (9%). Other treatment-emergent adverse reactions reported in >5% of patients treated with VIREAD included: abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain, and skin rash s In HBV-infected subjects with decompensated liver disease: Most common adverse reactions (all grades) reported in ≥10% of patients treated with VIREAD were abdominal pain (22%), nausea (20%), insomnia (18%), pruritus (16%), vomiting (13%), dizziness (13%), and pyrexia (11%)

Drug Interactions s Didanosine: Coadministration increases didanosine concentrations. Use with caution and monitor for evidence of didanosine toxicity (e.g., pancreatitis, neuropathy). Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions. In patients weighing >60 kg, the didanosine dose should be reduced to 250 mg once daily when it is coadministered with VIREAD and in patients weighing <60kg, the didanosine dose should be reduced to 200 mg once daily when coadministered with VIREAD

In clinical trials (Studies 102 and 103), no HBV resistance developed at Years 1, 2, 3, 4, 5, 6, or 7 in adult nucleoside-naïve patients with CHB and compensated liver disease.1,6

N0 HBV RESISTANCE DEVELOPED

YEAR 1 through YEAR 7 in clinical trials (Studies 102 and 103)1,6 s 68% (437/641) retention rate at Week 336: 283/426 patients given VIREAD—>VIREAD; 154/215 patients given adefovir dipivoxil —>VIREAD6

For more information, visit LearnAboutViread.com

Important Safety Information (cont’d) s HIV-1 protease inhibitors: Coadministration decreases ataazanavirr concenttrations and increases tenofovir concentrations; use ataazanavirr given with w ritonavir. Coadministration of VIREAD with ataazanavirr and ritoonavir, darunavir and ritonavir, or lopinavir/ritonavir inccreases tenofoviir concentrations. Monitor for evidence of tenofovir tooxicity s Drugs affecting renal function: Coadministration of VIREA AD with drugs that t reduce renal function or compete for active tubularr secretioon may increase concentrations of tenofovir

Dosage Adjustment for Patients with Altered Creatinine Clearance

Dosage and Administration

s Recommended dose, in adults and pediatric patients ≥12 years of age (≥35 kg), for the treatment of chronic hepatitis B: one 300 mg tablet, once daily, taken orally, without regard to food s In the treatment of chronic hepatitis B, the optimal duration of treatment is unknown s Safety and efﬁcacy in pediatric patients <12 years of age or weighing <35kg with chronic hepatitis B have not been established s The dosing interval of VIREAD should be adjusted (using recommendations in the table below) and renal function closely monitored in patients with baseline creatinine clearance <50 mL/min

Creatinine clearance (mL/min)a

Recommended 300 mg dosing interval a

Hemodialysis patients

≥50

30-49

10-29

Every 24 hours

Every 48 hours

Every 72 to 96 hours

Every 7 days or after a total of approximately 12 hours of dialysisb

Calculated using ideal (lean) body weight. Generally once weekly assuming three hemodialysis sessions a week of approximately 4 hours duration. VIREAD should be administered following completion of dialysis.

s The pharmacokinetics of tenofovir have not been evaluated in non-hemodialysis patients with creatinine clearance <10 mL/min; therefore, no dosing recommendation is available for these patients s No dose adjustment is necessary for patients with mild renal impairment (creatinine clearance 50-80 mL/min). Routine monitoring of estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein should be performed in these patients s No data are available to make dose recommendations in pediatric patients with renal impairment

Please see VIREAD Important Safety Information continued and Brief Summary of full Prescribing Information, including BOXED WARNING, on the following pages. References: 1. VIREAD Prescribing Information, Foster City, CA: Gilead Sciences, Inc.; October 2013. 2. Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. d 2008;359(23):2442-2455. 3. Data on file - Gilead Sciences, Inc. Study 102 CSR. 4. Data on file - Gilead Sciences, Inc. Study 103 CSR. 5. Marcellin P, Gane E, Bhuti M, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Published online December 10, 2012. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61425-1/fulltext. Accessed May 31, 2013. 6. Data on file - Gilead Sciences, Inc.

VIREAD® (tenofovir disoproxil fumarate) tablets Brief summary of full Prescribing Information. Please see full Prescribing Information including Boxed WARNING. Rx only WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS @ Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, in combination with other antiretrovirals (See Warnings and Precautions) @ Severe acute exacerbations of hepatitis have been reported in HBVinfected patients who have discontinued anti-hepatitis B therapy, including VIREAD. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy, including VIREAD. If appropriate, resumption of anti-hepatitis B therapy may be warranted (See Warnings and Precautions) INDICATIONS AND USAGE: VIREAD is indicated for the treatment of chronic hepatitis B in adults and pediatric patients 12 years of age and older The following points should be considered when initiating therapy with VIREAD for the treatment of HBV infection: J The indication in adults is based on safety and efficacy data from treatment of subjects who were nucleoside-treatment-naïve and subjects who were treatment-experienced with documented resistance to lamivudine. Subjects were adults with HBeAg-positive and HBeAg-negative chronic hepatitis B with compensated liver disease (See Adverse Reactions) J VIREAD was evaluated in a limited number of subjects with chronic hepatitis B and decompensated liver disease (See Adverse Reactions) J The numbers of subjects in clinical trials who had adefovir resistance-associated substitutions at baseline were too small to reach conclusions of efficacy DOSAGE AND ADMINISTRATION: For the treatment of chronic hepatitis B the recommended dose, in adults and pediatric patients ≥12 years of age (≥35 kg), is one 300 mg tablet, once daily, taken orally, without regard to food. In the treatment of chronic hepatitis B, the optimal duration of treatment is unknown. Safety and efficacy in pediatric patients <12 years of age with chronic hepatitis B weighing <35 kg have not been established. Dose Adjustment for Renal Impairment in Adults: Significantly increased drug exposures occurred when VIREAD was administered to subjects with moderate to severe renal impairment. Therefore, the dosing interval of VIREAD tablets 300 mg should be adjusted in patients with baseline creatinine clearance <50 mL/min using the recommendations in Table 1. These dosing interval recommendations are based on modeling of single-dose pharmacokinetic data in non-HIV and non-HBV infected subjects with varying degrees of renal impairment, including end-stage renal disease (ESRD) requiring hemodialysis. The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated in patients with moderate or severe renal impairment, therefore clinical response to treatment and renal function should be closely monitored in these patients (See Warnings and Precautions). No dose adjustment of VIREAD tablets 300 mg is necessary for patients with mild renal impairment (creatinine clearance 50–80 mL/min). Routine monitoring of estimated creatinine clearance, serum phosphorus, urine glucose and urine protein should be performed in patients with mild renal impairment (See Warnings and Precautions). Dosage Adjustment for Adult Patients with Altered Creatinine Clearance

Recommended 300 mg dosing interval

Creatinine clearance (mL/min)a ≥50 30-49 10-29

Hemodialysis patients

Every 24 Every 48 Every 72 to hours hours 96 hours

Every 7 days or after a total of approximately 12 hours of dialysisb

a. Calculated using ideal (lean) body weight. b. Generally once weekly assuming three hemodialysis sessions a week of approximately 4 hours duration. VIREAD should be administered following completion of dialysis. The pharmacokinetics of tenofovir have not been evaluated in non-hemodialysis patients with creatinine clearance <10 mL/min; therefore, no dosing recommendation is available for these patients. No data are available to make dose recommendations in pediatric patients with renal impairment. CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS: Lactic Acidosis/Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with VIREAD should be

suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). Exacerbation of Hepatitis after Discontinuation of Treatment: Discontinuation of anti-HBV therapy, including VIREAD, may be associated with severe acute exacerbations of hepatitis. Patients infected with HBV who discontinue VIREAD should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of anti-hepatitis B therapy may be warranted. New Onset or Worsening Renal Impairment: Tenofovir is principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of VIREAD (See Adverse Reactions). It is recommended that estimated creatinine clearance be assessed in all patients prior to initiating therapy and as clinically appropriate during therapy with VIREAD. In patients at risk of renal dysfunction, including patients who have previously experienced renal events while receiving adefovir dipivoxil , it is recommended that estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein be assessed prior to initiation of VIREAD, and periodically during VIREAD therapy. Dosing interval adjustment of VIREAD and close monitoring of renal function are recommended in all patients with creatinine clearance <50 mL/min (See Dosage and Administration). No safety or efficacy data are available in patients with renal impairment who received VIREAD using these dosing guidelines, so the potential benefit of VIREAD therapy should be assessed against the potential risk of renal toxicity. VIREAD should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple nonsteroidal anti-inflammatory drugs (NSAIDs)) (See Drug Interactions). Cases of acute renal failure after initiation of high dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on tenofovir DF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction. Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients. Coadministration with Other Products: VIREAD should not be used in combination with the fixeddose combination products ATRIPLA®, COMPLERA®, STRIBILD® or TRUVADA® since tenofovir disoproxil fumarate is a component of these products. VIREAD should not be administered in combination with adefovir dipivoxil (See Drug Interactions). Patients Coinfected with HIV-1 and HBV: Due to the risk of development of HIV-1 resistance, VIREAD should only be used in HIV-1 and HBV coinfected patients as part of an appropriate antiretroviral combination regimen. HIV-1 antibody testing should be offered to all HBV-infected patients before initiating therapy with VIREAD. It is also recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B before initiating treatment with VIREAD. Bone Effects Bone Mineral Density:: In clinical trials in HIV-1 infected adults, VIREAD was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving VIREAD (See Adverse Reactions). Clinical trials evaluating VIREAD in pediatric and adolescent subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects aged 2 years to less than 18 years, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the VIREAD-treated HIV-1 infected pediatric subjects as compared to the control groups. Similar trends were observed in chronic hepatitis B infected adolescent subjects aged 12 years to less than 18 years. In all pediatric trials, skeletal growth (height) appeared to be unaffected (See Adverse Reactions). The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for adults and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained. Mineralization Defects:: Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of VIREAD (See Adverse Reactions). Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing tenofovir DF (See Warnings and Precautions). ADVERSE REACTIONS: Clinical Trials in Adult Subjects with Chronic Hepatitis B and Compensated Liver Disease: Treatment-Emergent Adverse Reactions:: In controlled clinical trials in subjects with chronic hepatitis B (0102 and 0103), more subjects treated with VIREAD during the 48-week double-blind period experienced nausea: 9% with VIREAD versus 2% with adefovir dipivoxil. Other treatmentemergent adverse reactions reported in >5% of subjects treated with VIREAD included: abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain, and skin rash. No significant change in the tolerability profile was observed with continued treatment with VIREAD for up to 240 weeks. Laboratory Abnormalities:: in Studies 0102 and 0103 (0–48 Weeks) laboratory

Brief Summary (cont’d) abnormalities (Grades 3–4) reported in ≥1% of subjects treated with Viread (n=426) and adefovir dipivoxil (n=215), respectively, were: any ≥Grade 3 laboratory abnormality (19%, 13%); creatine kinase (M: >990 U/L; F: >845 U/L) (2%, 3%); serum amylase (>175 U/L) (4%, 1%); glycosuria (≥3+) (3%, <1%); AST (M: >180 U/L; F: >170 U/L) (4%, 4%); and ALT (M: >215 U/L; F: >170 U/L) (10%, 6%). Laboratory abnormalities (Grades 3–4) were similar in subjects continuing VIREAD treatment for up to 240 weeks in these trials. The overall incidence of on-treatment ALT flares (defined as serum ALT >2 × baseline and >10 × ULN, with or without associated symptoms) was similar between VIREAD (2.6%) and adefovir dipivoxil (2%). ALT flares generally occurred within the first 4-8 weeks of treatment and were accompanied by decreases in HBV DNA levels. No subject had evidence of decompensation. ALT flares typically resolved within 4-8 weeks without changes in study medication. The adverse reactions observed in subjects with chronic hepatitis B and lamivudine resistance who received treatment with VIREAD were consistent with those observed in other hepatitis B clinical trials in adults. Clinical Trial in Adult Subjects with Chronic Hepatitis B and Decompensated Liver Disease:: In a small randomized, double-blind, active-controlled trial (0108), subjects with CHB and decompensated liver disease received treatment with VIREAD or other antiviral drugs for up to 48 weeks. Among the 45 subjects receiving VIREAD, the most frequently reported treatment-emergent adverse reactions of any severity were abdominal pain (22%), nausea (20%), insomnia (18%), pruritus (16%), vomiting (13%), dizziness (13%), and pyrexia (11%). Two of 45 (4%) subjects died through Week 48 of the trial due to progression of liver disease. Three of 45 (7%) subjects discontinued treatment due to an adverse event. Four of 45 (9%) subjects experienced a confirmed increase in serum creatinine of 0.5 mg/dL (1 subject also had a confirmed serum phosphorus <2 mg/dL through Week 48). Three of these subjects (each of whom had a Child-Pugh score ≥10 and MELD score ≥14 at entry) developed renal failure. Because both VIREAD and decompensated liver disease may have an impact on renal function, the contribution of VIREAD to renal impairment in this population is difficult to ascertain. One of 45 subjects experienced an ontreatment hepatic flare during the 48 week trial. Clinical Trials in Pediatric Subjects 12 Years of Age and Older with Chronic Hepatitis B: Assessment of adverse reactions is based on one randomized study (0115) in 106 pediatric subjects (12 to less than 18 years of age) infected with chronic hepatitis B receiving treatment with VIREAD (N = 52) or placebo (N = 54) for 72 weeks. The adverse reactions observed in pediatric subjects who received treatment with VIREAD were consistent with those observed in clinical trials of VIREAD in adults. In this study, both the VIREAD and placebo treatment arms experienced an overall increase in mean lumbar spine BMD over 72 weeks, as expected for an adolescent population. The BMD gains from baseline to Week 72 in lumbar spine and total body BMD in VIREAD-treated subjects (+5% and +3%, respectively) were less than the BMD gains observed in placebo-treated subjects (+8% and +5%, respectively). Three subjects in the VIREAD group and two subjects in the placebo group had significant (greater than 4%) lumbar spine BMD loss at Week 72. At baseline, mean BMD Z-scores in subjects randomized to VIREAD were −0.43 for lumbar spine and −0.20 for total body, and mean BMD Z-scores in subjects randomized to placebo were −0.28 for lumbar spine and −0.26 for total body. In subjects receiving VIREAD for 72 weeks, the mean change in BMD Z-score was −0.05 for lumbar spine and −0.15 for total body compared to +0.07 and +0.06, respectively, in subjects receiving placebo. As observed in pediatric studies of HIV-infected patients, skeletal growth (height) appeared to be unaffected (See Warnings and Precautions). Postmarketing Experience: The following adverse reactions have been identified during postapproval use of VIREAD. Because postmarketing 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: allergic reaction, including angioedema, lactic acidosis, hypokalemia, hypophosphatemia, dyspnea, pancreatitis, increased amylase, abdominal pain, hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT), rash, rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy, acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria, asthenia. The following adverse reactions listed above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia. DRUG INTERACTIONS: Didanosine: Coadministration of VIREAD and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions. When administered with VIREAD, Cmaxx and AUC of didanosine increased significantly. The mechanism of this interaction is unknown. Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy. Suppression of CD4+ cell counts has been observed in patients receiving VIREAD with didanosine 400 mg daily. In patients weighing >60 kg, the didanosine dose should be reduced to 250 mg once daily when it is coadministered with VIREAD. In patients weighing <60 kg, the didanosine dose should be reduced to 200 mg once daily when it is coadministered with VIREAD. When coadministered, VIREAD and didanosine EC may be taken under fasted conditions or with a light meal (<400 kcal, 20% fat). For additional information on coadministration of VIREAD and didanosine, please refer to the full Prescribing Information for didanosine.

HIV-1 Protease Inhibitors: VIREAD decreases the AUC and Cmin of atazanavir. Viread should not be coadministered with atazanavir without ritonavir. Lopinavir/ritonavir, atazanavir coadministered with ritonavir, and darunavir coadministered with ritonavir have been shown to increase tenofovir concentrations. Tenofovir disoproxil fumarate is a substrate of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) transporters. When tenofovir disoproxil fumarate is co-administered with an inhibitor of these transporters, an increase in absorption may be observed. Patients receiving VIREAD concomitantly with lopinavir/ritonavir, ritonavir-boosted atazanavir, or ritonavir-boosted darunavir should be monitored for VIREAD-associated adverse reactions. VIREAD should be discontinued in patients who develop VIREAD-associated adverse reactions. Drugs Affecting Renal Function: Since tenofovir is primarily eliminated by the kidneys, coadministration of VIREAD with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of tenofovir and/or increase the concentrations of other renally eliminated drugs. Some examples include, but are not limited to cidofovir, acyclovir, valacyclovir, ganciclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs (See Warnings and Precautions). In the treatment of chronic hepatitis B, VIREAD should not be administered in combination with adefovir dipivoxil. USE IN SPECIFIC POPULATIONS: Pregnancy: Pregnancy Category B:: There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, VIREAD should be used during pregnancy only if clearly needed. Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to VIREAD, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263. Animal Data: Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir. Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. Samples of breast milk obtained from five HIV-1 infected mothers in the first post-partum week show that tenofovir is secreted in human milk. The impact of this exposure in breastfed infants is unknown. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving VIREAD. Geriatric Use: Clinical studies of VIREAD did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for the elderly patient should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Patients with Impaired Renal Function: It is recommended that the dosing interval for VIREAD be modified in patients with estimated creatinine clearance <50 mL/min or in patients with ESRD who require dialysis (See Dosage and Administration). For detailed information, please see full Prescribing Information. To learn more call 1-800-GILEAD-5 (1-800-445-3235) or visit www.VIREAD.com. COMPLERA, EMTRIVA, GSI, HEPSERA, STRIBILD, TRUVADA, and VIREAD are trademarks or registered trademarks of Gilead Sciences, Inc., or its related companies. ATRIPLA is a registered trademark of Bristol-Myers Squibb & Gilead Sciences, LLC. All other trademarks referenced herein are the property of their respective owners.

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

HBV Reactivation Preventable in Cancer Patients SAN FRANCISCO—Reactivation of hepatitis B infection is a threat to patients with cancer, and early intervention can prevent its sometimes fatal complications. Experts recommend screening all patients, assessing their risk for hepatitis and, for those at moderate or high risk for the disease, starting antiviral prophylaxis immediately. “In 2015, no cancer patients should be cured of their malignancy, only to die from reactivation of hepatitis B virus [HBV],” said Anna S. Lok, MD, the Alice Lohrman Andrews Professor in Hepatology and director of clinical hepatology at the University of Michigan, in Ann Arbor. At the 2015 Gastrointestinal Cancers Symposium, Dr. Lok described how immunosuppression induced by cancer treatment can abruptly increase viral replication, leading to hepatitis, acute liver failure and occasionally death. The dangerous complication can occur in patients who are surface-antigen positive (HBsAg+) or surfaceantigen negative (HBsAg–) and core antibody positive (anti-HBc+) with or without surface antibody. Reactivation has been most extensively studied in lymphoma—with the use of the anti-CD20 antibody rituximab—but it also occurs with other chemotherapy agents; corticosteroids in high enough doses; biologic therapies such as anti–tumor necrosis factor-α agents interleukin-17 and anti-CTLA4; and with more classic immunosuppressive agents such as methotrexate. According to case reports, even some molecularly targeted agents, including tyrosine kinase inhibitors

and the mTOR inhibitor everolimus, can cause HBV reactivation. Most of the data on the incidence of HBV reactivation in patients with cancer come from lymphoma. In one such study Dr. Lok conducted 25 years ago, she found HBV-related hepatitis in 48% of HBsAg+ lymphoma patients and in 4% of patients who were HBsAg– and anti-HBc+. Although elevated enzymes may seem “trivial,” she acknowledged, in her study of HBsAg+ patients 4% developed non-fatal liver failure and 4% died (Gastroenterologyy 1991;100:182-188). In a systematic review of patients receiving chemotherapy, HBV reactivation occurred in 38.7%, leading to hepatitis in 33%, liver failure in 13% and death in 5.5% of patients who did not receive antiviral prophylaxis (Ann Intern Med 2008;148:519-528). In another study of HBsAg+ patients, 30% experienced reactivation, including 58% with lymphoma and 25% with other malignancies, indicating that risks also exist for solid tumors (Br J Cancerr 2004;90:1306-1311).

Rituximab Greatest Concern Rituximab in the treatment of patients with lymphoma is the most worrisome when it comes to reactivation of HBV. Compared with regimens without the drug, rituximab increases the risk for reactivation more than fivefold among patients who are HBsAg–/antiHBc+. Reactivation can occur months, and even as long as years, after discontinuation of treatment. Therefore, long-term monitoring and prophylaxis with antivirals

Table. Risk-Based Prevention of HBV Reactivation Risk

HBsAg+

HBsAg-, anti-HBc+

Antiviral Therapy

High

Chemotherapy, anti-CD20 or anti-CD56 Rx; IST for transplantation; steroids in combination with other IST

Chemotherapy for hematologic malignancies, anti-CD20 or anti-CD56 Rx

Prophylaxis

Moderate

Anti-TNF Rx, maintenance low-dose steroids; other IST without steroid

Chemotherapy for solid tumors; IST for transplantation; steroids in combination with other IST

Prophylaxis or on-demand (monitor)

Low

Steroids alone for a few days

Anti-TNF, maintenance low-dose steroid, other IST without steroid

No prophylaxis

HBc, hepatitis B core antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; IST, immunosuppressive therapy; TNF, tumor necrosis factor

for 12 months after rituximab is stopped, is required, according to Dr. Lok. In 2013, after reports of 109 patient deaths associated with HBV reactivation after use of rituximab-containing regimens, the FDA warned clinicians to increase screening, monitoring and prophylaxis for the infection. Other risk factors for HBV reactivation include male sex; presence of high levels of HBV DNA at baseline; and the use of high-intensity immunosuppressive therapy conditioning regimens before bone marrow transplant, immunosuppressive therapy after solid organ transplant and high-dose steroids and anthracyclines. HBsAg+ patients are more at risk than HBsAg–/antiHBc+ patients.

Optimizing Prophylaxis Most of the data for preventing HBV reactivation are for lamivudine (Epivir, GlaxoSmithKline), the first approved oral nucleoside/nucleotide analogue. A systematic review of lamivudine ((Ann Intern Medd 2008;148:519528), involving 275 treated patients and 475 controls, found that the drug reduced HBV reactivation and HBV-related hepatitis by 79% to 100%; eliminated HBVrelated liver failure; reduced HBV-related deaths by 80% to 100%; and reduced cancer-related deaths significantly. “The reduction in death was observed because chemotherapy is often disrupted when reactivation occurred,” thus allowing tumor to rebound, Dr. Lok explained. Prophylactic use of the antiviral is preferred over treatment on demand once signs of reactivation appear. The preferred agents are entecavir and tenofovir, as these are the most potent viral suppressors and the least likely to cause drug resistance, Dr. Lok said. In a recent randomized controlled trial of patients treated with rituximab, entecavir was significantly more effective than lamivudine in HBsAg+ patients at preventing HBV reactivation (6.6% vs. 30%; P=0.001), P HBV-related hepatitis (0% vs. 13.3%; P P=0.003) and chemotherapy disruption (1.6% vs. 18.3%; P P=0.002) (JAMA 2014;312:2521-2530). Dr. Lok recently co-authored an algorithm for screening and prevention of HBV reactivation (Nat Rev Gastroenterol Hepatoll 2014;11:209-214), which she summarized at the meeting. She recommends screening all patients before starting immunosuppressive therapy, classifying them as 1) HBsAg+, 2) HBsAg–/anti-HBc+ and 3) HBsAg–/anti-HBc– and further stratifying the risk of the first two groups by HBV DNA levels. For HBsAg+ and HBsAg–/anti-HBc+ patients, those considered at high risk should receive a prophylactic antiviral; moderate-risk patients should receive prophylaxis or be monitored and receive on-demand antivirals; low-risk patients and patients who are both HBsAg– and antiHBc-negative should receive usual care (Table). Gregory Gores, MD, professor of medicine at Mayo Clinic, in Rochester, Minn., said: “There are probably a dozen different guidelines from multiple societies on the issue of HBV reactivation. The program committee of this meeting selected Dr. Lok to give her perspective because of her depth of knowledge in this topic and her pragmatic approach.” —Caroline Helwick Dr. Lok has held consulting or advisory roles for Gilead Sciences and GlaxoSmithKline, and has received research funding from Bristol-Myers Squibb and Gilead. Dr. Gores reported no relevant financial conflicts of interest.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

Good News for Obese Children (and Their Family and Friends): Being overweight does not appear to increase the body’s burden of methane-producing bacteria. lthough some evidence suggests that obese adults have elevated concentrations of methane in their breath, a new study has found that bacteria that make the gas are not triggering weight gain. The study included 338 children under age 19 years, of whom 60 were overweight and 50 were obese. The researchers, from Penn State Medical Center, in Hershey, compared methane production and body weight in the children, but found no connection. “No significant

correlation was observed for either overweight or obese children,” they reported. “The presence of methanogenic bacteria may not be part of the etiology of obesity or weight gain.” The researchers presented their findings at the 2014 annual meeting of the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition (abstract 140). ■

Patients Who Receive Steroids for IBD At Heightened Risk for Diabetes ining data from electronic health records (EHRs), researchers at Columbia University in New York City looked for a link between the use of steroids and blood sugar problems in 1,719 patients with inflammatory bowel disease (IBD). Of those patients, 698 had received glucocorticoid drugs. Among the steroid users, 140 (20%) developed steroidinduced diabetes compared with 21 patients (5.8%) who did not receive the drugs (odds ratio [OR], 7.42). More than one-fourth (27.5%) of patients with IBD who received steroids developed prediabetes compared with 67 of those (18.5%) who did not take the drugs (OR, 2.25). In addition to use of steroids, the researchers found that increasing age and intake of parenteral nutrition products raised the risk for diabetes, and that being male and using parenteral nutrition were risk factors for developing prediabetes. “To our knowledge, this is the first study to determine the prevalence and risk factors for [steroid-induced diabetes and prediabetes] in patients with IBD,” the researchers reported. “Gastroenterologists should be aware of the high prevalence” of these conditions in this population, “and should screen those treated with glucocorticoids for hyperglycemia. Using the EHR for automated detection of high-risk patients is possible and could result in earlier diagnosis, timelier treatment and possibly improved outcomes.” The researchers presented their findings at the 2014 annual meeting of the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition (abstract 369). ■

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Vaccine continued from page 22

clinical trials to test the efficacy of such a vaccine in humans, which they expect to begin as early as 2017. Dr. Houghton noted that another possible HCV vaccine is in Phase II clinical trials in the United States. The inoculation, developed by the Italian company Okairos, which recently was acquired by GlaxoSmithKline (GSK), is currently being tested in IV drug users, with the support of the National Institutes of Health. That vaccine differs markedly from the one Dr. Houghton and his colleagues will test in the clinic. In the current study, Dr. Houghton and his colleagues at the University of Alberta, together with a team at the Saint Louis University School of Medicine, in Missouri, purified the vaccine from mammalian cell lines, creating a recombinant protein to immunize goat and human antisera. The resulting vaccine produced antibodies that were found to target multiple strains of HCV—four to five out of seven known dominant genotypes. When the vaccine goes to trial, Dr. Houghton said, it will be as a “cocktail” of antigens that will, if successful, be capable of targeting all seven major HCV genotypes.

“Maybe their vaccine combined with our vaccine will be ideal,” he added. “We’ll have to see how it all plays out in the clinic.” Naglaa Shoukry, B Pharm, PhD, associate professor of medicine at the University of Montreal, in Quebec, Canada, an immunologist who has extensively studied T-cell response in HCV, said that Dr. Houghton’s study represents an important step forward for the field. She added that understanding both T-cell and antibody responses will be crucial to

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

developing a vaccine for HCV. Dr. Shoukry also stressed the importance of vaccine development over focusing exclusively on DAAs. “There is this circulating view that we don’t need a vaccine, because the drugs are so good,” she said. “That’s actually a misconception, and it’s dangerous to propagate this type of opinion. It’s great that we have those drugs, but it’s still very important to have a vaccine. “A lot of individuals within vulnerable populations who are at risk of getting

HCV don’t know they have it and just continue to spread it to others, or they live in situations where they do not have access to the proper care and hygiene that would prevent them from getting infected,” Dr. Shoukry continued. “A lot of people who inject drugs, a lot of people in prison, aboriginals, individuals who are infected with HIV, individuals in developing countries who do not have the means to use clean needles even for normal medical procedures.” —Ajai Raj

‘As recently as a few years ago, people were generally thinking in the field that HCV was going to be rather like HIV, insofar as being very difficult to be able to elicit antibodies from a vaccine that could neutralize or kill the infectivity of multiple viral strains.’ —Michael Houghton, PhD In contrast, the vaccine being tested by GSK on IV drug users—the population most at risk for, and most involved in the spread of, hepatitis C since screening hepatitis C out of the donor blood supply began—elicits only T-cell responses rather than also producing antibodies, according to Okairos. “If it works, it will be the first vaccine to work solely through the use of T-cell responses, without antibodies,” Dr. Houghton said. He noted that approximately one-fourth of patients who contract HCV spontaneously eradicate the virus, and that both T-cell and antibody responses have been observed in these patients. “Hopefully it will work. But our vaccine is designed to elicit the neutralizing antibodies as well as the T-cell responses. Only time will tell which one works and how well they work.

Up to 40% of p patients atients taking oral iron n suffer difficult-to-tolerate side effects1

IMPORTANT SAFETY INFORMATION ABOUT INJECTAFER® INDICATIONS/CONTRAINDICATIONS Injectafer® (ferric carboxymaltose injection) is an iron replacement product indicated for the treatment of iron deficiency anemia in adult patients who have intolerance to oral iron or have had unsatisfactory response to oral iron, and in adult patients with non-dialysis dependent chronic kidney disease. Injectafer® is contraindicated in patients with hypersensitivity to Injectafer® or any of its inactive components. WARNINGS AND PRECAUTIONS Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Injectafer®. Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. Monitor patients for signs and symptoms of hypersensitivity during and after Injectafer® administration for at least 30 minutes and until clinically stable

following completion of the infusion. Only administer Injectafer® when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. In clinical trials, serious anaphylactic/anaphylactoid reactions were reported in 0.1% (2/1775) of subjects receiving Injectafer®. Other serious or severe adverse reactions potentially associated with hypersensitivity which included, but were not limited to, pruritus, rash, urticaria, wheezing, or hypotension were reported in 1.5% (26/1775) of these subjects. In clinical studies, hypertension was reported in 3.8% (67/1775) of subjects. Transient elevations in systolic blood pressure, sometimes occurring with facial flushing, dizziness, or nausea were observed in 6% (106/1775) of subjects. These elevations generally occurred immediately after dosing and resolved within 30 minutes. Monitor patients for signs and symptoms of hypertension following each Injectafer® administration.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

PPIs Don’t Make Gut Microbes Run Amok in Peds hildren who take proton pump inhibitors (PPIs) chronically are not at increased risk for rampant growth of gut bacteria, researchers have found. Previous studies in adults have suggested—albeit inconclusively—that long-term use of PPIs may promote overgrowth of bacteria in the small intestine by interfering with the ability of gastric acid to regulate the flora. The new study, according to the researchers, is the first to ask the question in children.

The researchers, from Children’s Hospital of Michigan, in Detroit, studied 69 boys and girls under age 18 years, of whom 49 had been using PPIs chronically. Breath testing for hydrogen was abnormal in five of the children (10%) taking PPIs and one child (5%) in the non-PPI group, a statistically insignificant difference ((P=0.49), according to the investigators. “From our study, chronic proton pump inhibitor users were not found to have a statistically significant associated risk

for” bacterial overgrowth, the researchers reported. “This is an important finding, as proton pump inhibitors are readily prescribed in children.” The researchers presented their findings at the 2014 annual meeting of the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition (abstract 421). ■

In nflammation in IBD and malabsorption in post-gastric bypass and celiac disease may impair intestinal iron absorption Intravenous iron therapy with Injectafer® (ferric carboxym maltose injection) • The onlyy non-dextran IV iron approved in adult patien nts for the treatment of iron deficiency anemia (IDA) of various etiologies including: • IBD • celiac disease • bariatric surgery who are intolerant to or do not respond to oral iron • Avoids inflammation and malabsorption issues that may be exxperienced with IBD patients on oral iron2 • Avoids intestinal malabsorption with oral iron in celiac disease e and post-op gastric bypass patients3, 4 Saffety and Efficacy • No black box warning, no test dose or premedication required • Safety comparable to Venofer® (iron sucrose injection, USP)5 • Greater increases in Hb levels compared to oral iron or other IV V irons5

Inje ectafer® is indicated for the treatment of iron deficiency ane emia in adult patients who havve intolerance to oral iron or u unsatisfactory response to oraal iron

Transforming IV iron therap T py

www.injectafer.com In the 24 hours following administration of Injectafer®, laboratory assays may overestimate serum iron and transferrin bound iron by also measuring the iron in Injectafer®.

Please see Brief Summary of Full Prescribing Information on the following page.

ADVERSE REACTIONS In two randomized clinical studies, a total of 1775 patients were exposed to Injectafer®, 15 mg/kg of body weight, up to a single maximum dose of 750 mg of iron on two occasions, separated by at least 7 days, up to a cumulative dose of 1500 mg of iron. Adverse reactions reported by ≥2% of Injectafer®-treated patients were nausea (7.2%); hypertension (3.8%); flushing/hot flush (3.6%); blood phosphorus decrease (2.1%); and dizziness (2.0%).

REFERENCES 1. Crichton RR, Danielson BG, Geisser P. Iron Therapy With Special Emphasis on Intravenous Administration. 2nd ed. Bremen, Germany; UNI-MED Verlag AG.; 2005. 2. Zhu A, Kaneshiro M, Kaunitz. Evaluation and Treatment of Iron Deficiency Anemia: A Gastroenterological Perspective. Dig Dis Sci 2010;55(3):548–559. doi: 10.1007/ s10620-009-1108-6. Epub 2010 2010 Jan 27. 3. Hershko C, Patz J. Ironing out the mechanism of anemia in celiac disease. Haematologica. 2008;93(12):1761-1765. doi:10.3324/haematol.2008.000828. 4. Gesquiere I, Lannoo M, Augustijns P, Matthys C, Van der Schueren B, Foulon V. Iron deficiency after Roux-en-Y gastric bypass: insufficent iron absorption from oral iron supplements. Obes Surg. 2014;24:56-61. doi: 10.1007/s11695-013-1042-8. 5. Onken JE, Bregman DB, Harrington RA, et al. A multicenter, randomized, active-controlled study to investigate the efficacy and safety of intravenous ferric carboxymaltose in patients with iron deficiency anemia. Transfusion. 2014;54(2):306-15. doi: 10.1111/trf.12289. Epub 2013 Jun 17. ®

The following serious adverse reactions have been most commonly reported from the post-marketing spontaneous reports: urticaria, dyspnea, pruritus, tachycardia, erythema, pyrexia, chest discomfort, chills, angioedema, back pain, arthralgia, and syncope.

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

GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ MAY 2015

Long-Term Use of Aspirin May Prevent NAFLD PHILADELPHIAâ&#x20AC;&#x201D;Animal studies have found that aspirin and other antiplatelet agents are effective in treating oxidative stress, liver inflammation and insulin resistance associated with nonalcoholic fatty liver disease (NAFLD). New research suggests aspirin may protect against the development of NAFLD in humans, too. â&#x20AC;&#x153;This is the first human study to investigate an association between aspirin and NAFLD, and our results suggest that

regular aspirin use may be associated with a lower prevalence of NAFLD, primarily among men and older patients,â&#x20AC;? said Huafeng Shen, MD, a third-year resident at the Nassau University Medical Center in East Meadow, N.Y. To investigate their hypothesis that use of aspirin may be inversely associated with NAFLD, Dr. Shen and his colleagues examined data from the third National Health and Nutrition Examination Survey (NHANES III) on 11,416

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s WHO HAVE NON DIALYSIS DEPENDENT CHRONIC KIDNEY DISEASE +6:(., (5+ (+4050:;9(;065! &OR PATIENTS WEIGHING KG LB OR MORE 'IVE InjectaferÂŽ IN TWO DOSES SEPARATED BY AT LEAST DAYS 'IVE EACH DOSE AS MG FOR A TOTAL CUMULATIVE DOSE NOT TO EXCEED MG OF IRON PER COURSE &OR PATIENTS WEIGHING LESS THAN KG LB 'IVE )NJECTAFERÂŽ IN TWO DOSES SEPARATED BY AT LEAST DAYS 'IVE EACH DOSE AS MG KG BODY WEIGHT FOR A TOTAL CUMULATIVE DOSE NOT TO EXCEED MG OF IRON PER COURSE InjectaferÂŽ TREATMENT MAY BE REPEATED IF IRON DElCIENCY ANEMIA REOCCURS Administer InjectaferÂŽ INTRAVENOUSLY EITHER AS AN UNDILUTED SLOW INTRAVENOUS PUSH OR BY INFUSION 7HEN ADMINISTERING AS A SLOW INTRAVENOUS PUSH GIVE AT THE RATE OF APPROXIMATELY MG M, PER MINUTE 7HEN ADMINISTERED VIA INFUSION DILUTE UP TO MG OF IRON IN NO MORE THAN M, OF STERILE SODIUM CHLORIDE INJECTION 530 SUCH THAT THE CONCENTRATION 0 OF THE INFUSION IS NOT LESS THAN MG OF IRON PER M, AND ADMINISTER OVER AT LEAST MINUTES )NSPECT PARENTERAL DRUG PRODUCTS VISUALLY FOR THE ABSENCE OF PARTICULATE MATTER AND DISCOLORATION PRIOR TO ADMINISTRATION 4HE PRODUCT CONTAINS NO PRESERVATIVES )NJECTAFERÂŽ is a SINGLE USE VIAL $ISCARD UNUSED PORTION !VOID EXTRAVASATION OF )NJECTAFERÂŽ SINCE BROWN DISCOLORATION OF THE EXTRAVASATION SITE MAY BE LONG LASTING -ONITOR FOR EXTRAVASATION )F EXTRAVASATION OCCURS DISCONTINUE THE )NJECTAFERÂŽ ADMINISTRATION AT THAT SITE +6:(., -694: (5+ :;9,5.;/:! 3INGLE USE VIALS CONTAINING MG ELEMENTAL IRON PER M, IN THE FOLLOWING PRESENTATION MG IRON M, *65;9(05+0*(;065:! (YPERSENSITIVITY TO )NJECTAFERÂŽ OR ANY OF ITS INACTIVE COMPONENTS >(9505.: (5+ 79,*(<;065: /`WLYZLUZP[P]P[` 9LHJ[PVUZ! Serious hypersensitivity reactions, including anaphylactictype reactions, some of which have been life-threatening and fatal, have been reported in patients receiving InjectaferÂŽ. Patients may present with shock, clinically signiďŹ cant hypotension, loss of consciousness, and/or collapse. Monitor patients for signs and symptoms of hypersensitivity during and after InjectaferrÂŽ administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer InjectaferÂŽ when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. )N CLINICAL TRIALS SERIOUS ANAPHYLACTIC ANAPHYLACTOID REACTIONS WERE REPORTED IN OF SUBJECTS RECEIVING )NJECTAFERRÂŽ /THER SERIOUS OR SEVERE ADVERSE REACTIONS POTENTIALLY ASSOCIATED WITH HYPERSENSITIVITY WHICH INCLUDED BUT NOT LIMITED TO PRURITUS

RASH URTICARIA WHEEZING OR HYPOTENSION WERE REPORTED IN OF THESE SUBJECTS /`WLY[LUZPVU! )N CLINICAL STUDIES HYPERTENSION WAS REPORTED IN OF SUBJECTS IN CLINICAL TRIALS AND 4RANSIENT ELEVATIONS IN SYSTOLIC BLOOD PRESSURE SOMETIMES OCCURRING WITH FACIAL mUSHING DIZZINESS OR NAUSEA WERE OBSERVED IN OF SUBJECTS IN THESE TWO CLINICAL TRIALS 4HESE ELEVATIONS GENERALLY OCCURRED IMMEDIATELY AFTER DOSING AND RESOLVED WITHIN MINUTES -ONITOR PATIENTS FOR SIGNS AND SYMPTOMS OF HYPERTENSION FOLLOWING EACH InjectaferÂŽ ADMINISTRATION 3HIVYH[VY` ;LZ[ (S[LYH[PVUZ! )N THE HOURS FOLLOWING ADMINISTRATION OF )NJECTAFERÂŽ

LABORATORY ASSAYS MAY OVERESTIMATE SERUM IRON AND TRANSFERRIN BOUND IRON BY ALSO MEASURING the iron in InjectaferÂŽ (+=,9:, 9,(*;065: (K]LYZL 9LHJ[PVUZ PU *SPUPJHS ;YPHSZ! "ECAUSE CLINICAL TRIALS ARE CONDUCTED UNDER WIDELY VARYING CONDITIONS THE ADVERSE REACTION RATES OBSERVED CANNOT BE DIRECTLY COMPARED TO RATES IN OTHER CLINICAL TRIALS AND MAY NOT REmECT THE RATES OBSERVED IN CLINICAL PRACTICE )N TWO RANDOMIZED CLINICAL STUDIES A TOTAL OF PATIENTS WERE EXPOSED TO )NJECTAFERÂŽ MG KG BODY WEIGHT UP TO A MAXIMUM SINGLE DOSE OF MG OF IRON ON TWO OCCASIONS SEPARATED BY AT LEAST DAYS UP TO A CUMULATIVE DOSE OF MG OF IRON !DVERSE REACTIONS REPORTED BY * OF TREATED PATIENTS ARE SHOWN IN THE FOLLOWING TABLE 4ABLE !DVERSE REACTIONS REPORTED IN * OF 3TUDY 0ATIENTS IN #LINICAL 4RIALS AND InjectaferÂŽ 0OOLED #OMPARATORSa . . .AUSEA Hypertension &LUSHING (OT &LUSH "LOOD 0HOSPHORUS $ECREASE $IZZINESS 6OMITING )NJECTION 3ITE $ISCOLORATION Headache Alanine Aminotransferase Increase $YSGEUSIA Hypotension #ONSTIPATION a Includes oral iron and all formulations of IV iron other than InjectaferÂŽ 4ERM

/RAL IRON .

4RANSIENT DECREASES IN LABORATORY BLOOD PHOSPHORUS LEVELS MG D, HAVE BEEN OBSERVED IN OF PATIENTS IN CLINICAL TRIALS

men and women aged 20 to 74 years who underwent ultrasonography. They identified 2,889 individuals with NAFLD diagnosed by ultrasound; the remaining 8,527 did not have the condition. The subjects were divided into three groups: those who never used aspirin; occasional aspirin users, defined as one to 14 times per month; and regular aspirin users, defined as more than 15 times per month. Dosage information was not available.

(K]LYZL 9LHJ[PVUZ MYVT 7VZ[ THYRL[PUN ,_WLYPLUJL! 4HE FOLLOWING SERIOUS ADVERSE REACTIONS HAVE BEEN MOST COMMONLY REPORTED FROM THE POST MARKETING SPONTANEOUS REPORTS WITH )NJECTAFERÂŽ URTICARIA DYSPNEA PRURITUS TACHYCARDIA ERYTHEMA PYREXIA CHEST DISCOMFORT CHILLS ANGIOEDEMA BACK PAIN ARTHRALGIA AND SYNCOPE /NE CASE OF HYPOPHOSPHATEMIC OSTEOMALACIA WAS REPORTED IN A SUBJECT WHO RECEIVED MG OF )NJECTAFERÂŽ EVERY WEEKS FOR A TOTAL OF WEEKS 0ARTIAL RECOVERY FOLLOWED DISCONTINUATION OF )NJECTAFERÂŽ +9<. 05;,9(*;065:! &ORMAL DRUG INTERACTION STUDIES HAVE NOT BEEN PERFORMED WITH )NJECTAFERÂŽ <:, 05 :7,*0-0* 767<3(;065: 7YLNUHUJ` 0REGNANCY #ATEGORY # !DEQUATE AND WELL CONTROLLED STUDIES IN PREGNANT WOMEN HAVE NOT BEEN CONDUCTED )NJECTAFERÂŽ SHOULD BE USED DURING PREGNANCY ONLY IF THE POTENTIAL BENElT JUSTIlES THE POTENTIAL RISK TO THE FETUS 5\YZPUN 4V[OLYZ! ! STUDY TO DETERMINE IRON CONCENTRATIONS IN BREAST MILK AFTER ADMINISTRATION of InjectaferÂŽ N OR ORAL FERROUS SULFATE N WAS CONDUCTED IN LACTATING WOMEN WITH POSTPARTUM IRON DElCIENCY ANEMIA -EAN BREAST MILK IRON LEVELS WERE HIGHER IN LACTATING WOMEN RECEIVING )NJECTAFERÂŽ THAN IN LACTATING WOMEN RECEIVING ORAL FERROUS SULFATE 7LKPH[YPJ <ZL! 3AFETY AND EFFECTIVENESS HAS NOT BEEN ESTABLISHED IN PEDIATRIC PATIENTS .LYPH[YPJ <ZL! /F THE SUBJECTS IN CLINICAL STUDIES OF )NJECTAFERÂŽ WERE YEARS AND OVER WHILE WERE YEARS AND OVER .O OVERALL DIFFERENCES IN SAFETY OR EFFECTIVENESS WERE OBSERVED BETWEEN THESE SUBJECTS AND YOUNGER SUBJECTS AND OTHER REPORTED CLINICAL EXPERIENCE HAS NOT IDENTIlED DIFFERENCES IN RESPONSES BETWEEN THE ELDERLY AND YOUNGER PATIENTS BUT GREATER SENSITIVITY OF SOME OLDER INDIVIDUALS CANNOT BE RULED OUT 6=,9+6:(.,! %XCESSIVE DOSAGES OF )NJECTAFERÂŽ MAY LEAD TO ACCUMULATION OF IRON IN STORAGE SITES POTENTIALLY LEADING TO HEMOSIDEROSIS ! PATIENT WHO RECEIVED )NJECTAFERÂŽ MG OVER MONTHS DEVELOPED HEMOSIDEROSIS WITH MULTIPLE JOINT DISORDER WALKING DISABILITY AND ASTHENIA (YPOPHOSPHATEMIC OSTEOMALACIA WAS REPORTED IN A PATIENT WHO RECEIVED )NJECTAFERÂŽ MG OVER MONTHS 0ARTIAL RECOVERY FOLLOWED DISCONTINUATION OF )NJECTAFERÂŽ +,:*907;065! Ferric carboxymaltose, an iron replacement product, is an iron carbohydrate complex with the chemical name of polynuclear iron (III) hydroxide O ÄŽ-D-glucopyranosyl)-oxy-2(R),3(S),5(R),6-tetrahydroxy-hexanoate. 4(R)-(poly-(1Äş4)-OIt has a relative molecular weight of approximately 150,000 Da. InjectaferÂŽ FERRIC CARBOXYMALTOSE INJECTION IS A DARK BROWN STERILE AQUEOUS ISOTONIC COLLOIDAL SOLUTION FOR INTRAVENOUS INJECTION %ACH M, CONTAINS MG IRON AS FERRIC CARBOXYMALTOSE IN WATER FOR INJECTION 3ODIUM HYDROXIDE AND OR HYDROCHLORIC ACID MAY HAVE BEEN ADDED TO ADJUST THE P( TO 4HE VIAL CLOSURE IS NOT MADE WITH NATURAL RUBBER LATEX *3050*(3 7/(94(*636.@ 4LJOHUPZT VM (J[PVU! Ferric carboxymaltose is a colloidal iron (III) hydroxide in complex WITH CARBOXYMALTOSE A CARBOHYDRATE POLYMER THAT RELEASES IRON 7OHYTHJVK`UHTPJZ! 5SING POSITRON EMISSION TOMOGRAPHY 0%4 IT WAS DEMONSTRATED THAT RED CELL UPTAKE OF Fe and Fe from InjectaferÂŽ RANGED FROM TO )N PATIENTS WITH IRON DElCIENCY RED CELL UPTAKE OF RADIO LABELED IRON RANGED FROM TO AFTER DAYS InjectaferÂŽ DOSE )N PATIENTS WITH RENAL ANEMIA RED CELL UPTAKE OF RADIO LABELED IRON RANGED FROM TO AFTER DAYS )NJECTAFERÂŽ DOSE 7OHYTHJVRPUL[PJZ! !FTER ADMINISTRATION OF A SINGLE DOSE OF )NJECTAFERÂŽ OF TO MG OF IRON IN IRON DElCIENT PATIENTS MAXIMUM IRON LEVELS OF ÂŤG M, TO ÂŤG M, WERE OBTAINED RESPECTIVELY AFTER MINUTES TO HOURS POST DOSE 4HE VOLUME OF DISTRIBUTION WAS ESTIMATED TO BE , 4HE IRON INJECTED OR INFUSED WAS RAPIDLY CLEARED FROM THE PLASMA THE TERMINAL HALF LIFE RANGED FROM TO HOURS 2ENAL ELIMINATION OF IRON WAS NEGLIGIBLE 565*3050*(3 ;6?0*636.@ *HYJPUVNLULZPZ 4\[HNLULZPZ HUK 0TWHPYTLU[ VM -LY[PSP[`! #ARCINOGENICITY STUDIES HAVE NOT BEEN PERFORMED WITH FERRIC CARBOXYMALTOSE &ERRIC CARBOXYMALTOSE WAS NOT GENOTOXIC IN THE FOLLOWING GENETIC TOXICOLOGY STUDIES in vitro o MICROBIAL MUTAGENESIS !MES ASSAY in vitroo chromosome aberration test in human LYMPHOCYTES in vitro MAMMALIAN CELL MUTATION ASSAY IN MOUSE LYMPHOMA , 9 4+ C o ELLS in vivoo MOUSE MICRONUCLEUS TEST AT SINGLE INTRAVENOUS DOSES UP TO MG KG )N A COMBINED MALE AND FEMALE FERTILITY STUDY FERRIC CARBOXYMALTOSE WAS ADMINISTERED INTRAVENOUSLY OVER ONE HOUR TO MALE AND FEMALE RATS AT IRON DOSES OF UP TO MG KG !NIMALS WERE DOSED TIMES PER WEEK ON $AYS AND 4HERE WAS NO EFFECT ON MATING FUNCTION

FERTILITY OR EARLY EMBRYONIC DEVELOPMENT 4HE DOSE OF MG KG IN ANIMALS IS APPROXIMATELY OF THE HUMAN DOSE OF MG BASED ON BODY SURFACE AREA *3050*(3 :;<+0,:! 4HE SAFETY AND EFlCACY OF )NJECTAFERÂŽ for treatment of iron deďŹ ciency ANEMIA WERE EVALUATED IN TWO RANDOMIZED OPEN LABEL CONTROLLED CLINICAL TRIALS 4RIAL AND 4RIAL )N THESE TWO TRIALS )NJECTAFERÂŽ WAS ADMINISTERED AT DOSE OF MG KG BODY WEIGHT UP TO A MAXIMUM SINGLE DOSE OF MG OF IRON ON TWO OCCASIONS SEPARATED BY AT LEAST DAYS UP TO A CUMULATIVE DOSE OF MG OF IRON 7(;0,5; *6<5:,305. 05-694(;065 s 1UESTION PATIENTS REGARDING ANY PRIOR HISTORY OF REACTIONS TO PARENTERAL IRON PRODUCTS s !DVISE PATIENTS OF THE RISKS ASSOCIATED WITH )NJECTAFERÂŽ s !DVISE PATIENTS TO REPORT ANY SIGNS AND SYMPTOMS OF HYPERSENSITIVITY THAT MAY DEVELOP DURING AND FOLLOWING )NJECTAFERÂŽ ADMINISTRATION SUCH AS RASH ITCHING DIZZINESS

LIGHTHEADEDNESS SWELLING AND BREATHING PROBLEMS InjectaferÂŽ IS MANUFACTURED UNDER LICENSE FROM 6IFOR )NTERNATIONAL )NC 3WITZERLAND

)SS

After adjusting for factors including age, sex, body mass index, insulin resistance and blood pressure, the researchers found that patients with NAFLD were less likely than the other participants to be regular users of aspirin, 7.7% and 8.9%, respectively (odds ratio, 0.62; P=0.04). P When the researchers stratified by sex, however, they discovered the association between aspirin use and lower prevalence of NAFLD applied only to men. Furthermore, the association was stronger in participants over age 60 years. Why this should be is not entirely clear, but Dr. Shen offered a theory.

â&#x20AC;&#x153;Based on previous pharmacokinetic studies, weâ&#x20AC;&#x2122;ve found women to have more urinary excretions of aspirin and its metabolites than men, and younger subjects have a higher clearance of aspirin than older subjects, so we think younger and female patients may require higher aspirin doses to achieve a protective effect against NAFLD,â&#x20AC;? he said. As to why aspirin has a protective effect at all, Dr. Shen proposed a few explanations. â&#x20AC;&#x153;Aspirin can stimulate vascular endothelial growth factor, leading to antioxidant activity. It can also inhibit tumor necrosis factor-alpha, which causes liver inflammation and fibrosis,â&#x20AC;? he said, noting that aspirin also appears to have a positive effect on insulin sensitivity. â&#x20AC;&#x153;Our findings suggest that regular aspirin use may be associated with a lower prevalence of NAFLD in men and older see Prevent, page 34

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

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

Study Suggests 12-Week Option for Some HCV Patients BOSTON— —Twelve weeks of the fixed-dose combination “However, among treatment-experienced patients, 12 and the use of ribavirin resulted in more frequent adverse ledipasvir-sofosbuvir (Harvoni, Gilead) plus ribavirin is weeks of ledipasvir-sofosbuvir resulted in a 90% SVR events and declines in hemoglobin,” Dr. Bourlière said. as effective as 24 weeks of the therapy in certain patients rate, and adding ribavirin or extending treatment duraHe said it was time to start using the shortened regiwith hepatitis C, according to new data that suggest the tion up to 24 weeks increased this rate to more than men in clinical practice. “When we look at this data, we abbreviated course could be a less expensive option for 96%,” Dr. Bourlière said. “This difference is not statisti- need to move the treatment paradigm,” Dr. Bourlière said. those with advanced illness. cally significant, but it is a trend.” —Kate O’Rourke The findings, presented at the 2014 Liver Meeting of Only 8% of patients experienced adverse events con- Dr. Bourlière disclosed numerous financial relationships including board membership with Gilead. Dr. Lindor reported no relevant the American Association for the Study of Liver Dis- sidered to be serious (Table 3). “Ledipasvir-sofosbuvir financial conflicts of interest. eases (AASLD; abstract 82), showed that the shorter was safe and well tolerated in patients with cirrhosis, course of Harvoni produced strong cure rates in treatment-experienced patients with genotype 1 hepatitis C virus (HCV) and cirrhosis. “This study suggests that 12 weeks of the regimen plus ribavirin might be enough,” said Marc Bourlière, MD, head of the Hepato-Gastroenterology Department at Hospital Saint-Joseph in Marseilles, France, who presented the findings. Experts said the study should spur clinicians to use 12 weeks of ledipasvir-sofosbuvir plus ribavirin in treatment-experienced patients with HCV and cirrhosis. “This is important new information, which will quickly find its place in practice,” said Keith Lindor, MD, president of the AASLD. In October 2014, the FDA approved ledipasvirsofosbuvir for the treatment of chronic HCV genotype 1 infection. The drug was approved for 12 weeks in Table 1. Platelet Counts, Cirrhosis Determination and Albumin Levels treatment-naive patients with or without cirrhosis; 12 weeks for treatment-experienced patients without cirTreatment-Naive, Treatment-Experienced, Total Population, % rhosis; and 24 weeks for treatment-experienced patients % (n=161) % (n=352) (N=513) with cirrhosis. Platelet count, mcL According to Gilead, the wholesale price is $1,125 <75,000 6 8 7 per one daily Harvoni tablet or approximately $189,000 for 24 weeks of ledipasvir-sofosbuvir treatment. Adop<100,000 21 22 22 tion of a shorter regimen in this patient population <125,000 47 43 44 would significantly cut treatment costs. In the United Cirrhosis determination method States, the price of 12 weeks of ledipasvir-sofosbuvir Liver biopsy 45 48 47 plus ribavirin is less than $100,000, Dr. Lindor said. In the new study, investigators conducted a pooled Fibroscan >12.5 kPa 40 45 44 analysis of 513 patients with genotype 1 HCV and comFibroTest >0.75 + APRI >2 15 7 9 pensated cirrhosis who had received ledipasvir-sofosbuvir Albumin <3.5 g/dL 13 12 12 with or without ribavirin as part of seven Phase II and III APRI, aspartate aminotransferase-to-platelet ratio index trials: LONESTAR, ELECTRON, ELECTRON-2, GS-US-337-0113 ( Japan), ION-1, ION-2 and SIRIUS. Table 2. SVR Rates at Week 12 The cohort included 352 treatment-experienced patients and 161 treatment-naive patients (Table 1). The SVR in Treatment-Naive SVR in Treatmentaverage age in the pooled patients was 58 years, and 67% Patients, % Experienced Patients, % were male. Patients were primarily white with 5% black LDV/SOF 12 wk 96 90 and 15% Asian. The average body mass index was 28 kg/ LDV/SOF + RBV 12 wk 98 96 m2. Sixty percent of patients had genotype 1a HCV. LDV/SOF 24 wk 97 98 Overall, in the seven studies, the rate of sustained virologic response (SVR) at week 12 was 96%, with 20 LDV/SOF + RBV 24 wk 100 100 patients failing to reach that mark (Table 2). Eighteen LDV/SOF, ledipasvir/sofosbuvir; RBV, ribavirin; SVR, sustained virologic response patients relapsed and one patient died, presumably of infection, according to the researchers. Laboratory test Table 3. Comparison of Treatment Safety results—albumin levels, alanine transaminase, bilirubin and platelets counts—reflected improvements in liver Drug Effect Patients Receiving LDV/ Patients Receiving function, the investigators said. SOF for 12 and 24 wk, % LDV/SOF + RBV for 12 and 24 wk, % “High rates of SVR were observed in all subgroups,” Dr. Bourlière said. “Overall, there was no significant Treatment-related AE 47 75 statistical difference between patients treated for 12 or Grade ≥3 AE 8 8 24 weeks and those treated with or without ribavirin.” Serious AE 6 3 Age, prior treatment and the severity of liver disTreatment-related serious AE <1 2 ease did not affect the SVR rate. The only characteristic that had a statistically significant effect on SVR AE leading to study modification/interruption 1 15 rate was platelet count; patients with a platelet count Grade 3/4 laboratory abnormalities 16 13 below 75,000/mcL had a lower SVR rate than those with higher counts. AE, adverse event; LDV/SOF, ledipasvir/sofosbuvir; RBV, ribavirin

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

VA continued from page 1

The study found that a large number of patients who had a positive hepatitis B surface antigen (HBsAg) test did not receive the additional tests recommended by guidelines from the American Association for the Study of Liver Diseases (AASLD). About 60% of vets who should have been treated for chronic hepatitis B infection received treatment for the illness, according to the new study, which researchers presented at the AASLD’s 2014 Liver Meeting (abstract 68). The VA is the largest provider of hepatitis care in the United States. AASLD President Adrian Di Bisceglie, MD, who was not involved with the study, said the results are most likely not specific to veterans, and that overall adherence to the hepatitis B guidelines in the United States is low. “I really believe, based on our own experience, that what is described here within the VA system is mirrored in the rest of the country,” Dr. Di Bisceglie said. “We need to raise awareness about this.” The 2009 AASLD Practice Guidelines for Management of Chronic Hepatitis B recommend hepatitis B virus (HBV) screening for people born in countries where the virus is hyperendemic, men who have sex with men, IV drug users and a variety of other subgroups (Table 1). HBsAg is the initial screening test for detection of acute and chronic HBV infection. If this test is positive, the AASLD recommends additional serologic and biochemical testing to determine treatment. Few data exist on whether clinicians are following these guidelines, but several small studies suggest poor adherence ((Am J Gastroenteroll 2014;109:867-875). In the new study, David E. Kaplan, MD, director of hepatology at the Philadelphia VA Medical Center, and University of Pennsylvania colleagues Marina Serper, MD, and Kimberly Forde, MD, MPH, analyzed data from the VHA Corporate Data Warehouse to identify adult patients with any positive HBsAg result from 1999 to 2013. They looked at whether many of these patients received the recommended additional virus tests and liver panel including HBV DNA and alanine transaminase. Of the 2.6 million veterans who underwent HBsAg screening, 1.9% had a positive test and 95.2% were new diagnoses. Although every patient with a positive HBsAg test should undergo a battery of other tests, the percentage that did ranged from 26% to 73% (Table 2). Those who received care from a specialist were more likely to receive the recommended tests. In veterans diagnosed with hepatitis B, the researchers identified low rates of HBV antiviral treatment (25%), screening for hepatocellular carcinoma (HCC; 13%)

Prevent continued from page 32

people,” said Dr. Shen, who presented the findings at the 2014 meeting of the American College of Gastroenterology (abstract 28). The full manuscript was published in Alimentary Pharmacology & Therapeutics (2014;40:1066-1073). However, James Lewis, MD, professor of medicine at the Georgetown School of Medicine in Washington, D.C., questioned whether the study was relevant

‘I really believe, based on our own experience, that what is described here within the VA system is mirrored in the rest of the country. We need to raise awareness about this.’ —Adrian Di Bisceglie, MD

Table 1. Populations That Should Receive Hepatitis B Screening HBV hyperendemic areas including Africa, South Asia (except Sri Lanka), European Mediterranean, eastern Europe, parts of South America and the Caribbean, the Middle East (except Cyprus) Men who have sex with men IV drug users Dialysis patients HIV-infected individuals Pregnant women Family members, household members and sexual contacts of HBV-infected persons HBV,, hepatitis epa s B virus us

Table 2. Percentage of Patients Receiving Recommended Testing Test

Patients With a Positive HBsAg Total Patients With Positive HBsAg, %

Patients Not Receiving Specialized Care, %

Patients Receiving Specialized Care, %

Alanine transaminase

Hepatitis B virus DNA

Hepatitis B e antigen

Hepatitis B e antibody

HBsAg, s g, hepatitis epa s B surface su ace antigen a ge e

and vaccination against hepatitis A virus (1.8%). Lack of antiviral therapy and HCC screening increased the risk for death. “Only about 60% of individuals for whom treatment would likely be appropriate actually received treatment,” Dr. Kaplan said. AASLD guidelines recommend that patients with a positive HBsAg test also receive tests to rule out several viral coinfections: hepatitis C; antibodies against the hepatitis D virus (HDV) in individuals from countries where that infection is common and in those with history of IV drug use; and HIV in those at risk for the infection. But some clinicians believe all HBsAg-positive patients receive these tests. “We know that clinicians are very poor at eliciting accurate histories of prior injection drug use. Furthermore, rates of HDV in Asians are similar to those in non-Asian

considering it was based on data from NHANES III, which was conducted between 1988 and 1994. Dr. Lewis was not involved in the study. “With the rise in the prevalence of diabetes and obesity over the past two decades, the results from data more than 20 years old may not be as pertinent or representative as a prospectively designed study done today,” Dr. Lewis said. “Given the study’s acknowledged limitations, it seems their results would

populations, yet Asians would not be considered from countries were HDV infection is considered common,” Dr. Kaplan said. “For these reasons, we recommend that updated versions of the AASLD guidelines include a recommendation for one-time testing in all patients with chronic HBV for HCV, HIV and HDV, rather than the current risk-based recommendation.” In the VA study, 78.2% of veterans received a test for hepatitis C, 33.2% received an HIV test and 4.1% received a test for HDV. There is a need, Dr. Kaplan said, for “implementation and testing of clinical decision support tools to improve guideline adherence and clinical outcomes in HBV.” —Kate O’Rourke Drs. Kaplan and Di Bisceglie reported no relevant financial conflicts of interest.

be best interpreted only as rational to perform a definitive prospective randomized controlled trial, or to at least repeat the analysis using more current data.” Suthat Liangpunsakul, MD, associate professor of medicine at Indiana University, in Indianapolis, found the study interesting, but also noted that its design limits its utility. “Gender differences on the effect of aspirin on prevalence of NAFLD is an interesting observation, but as with any

cross-sectional study, we have to be cautious with the interpretation. Causality cannot be drawn on whether aspirin intake truly reduced the long-term risk for NAFLD,” Dr. Liangpunsakul said. “And although the authors suggest that prospective randomized controlled trials are needed to determine the effect of aspirin on the prevention of NAFLD, such studies might be too cost-prohibitive to perform.” —Monica J. Smith

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

New Hep C Drugs Offer Hope to Sickest Patients PHILADELPHIA—Even the sickest patients with hepatitis C infection— those with compensated cirrhosis— appear to reap the benefits of the new oral regimens, achieving such high cure rates that researchers are now able to evaluate the treatment’s impact on liver injury and liver function. The researchers reported that patients with cirrhosis who took the oral medications experienced early improvements in measures of hepatic injury and liver function, and possibly portal hypertension, although studies of longer duration are needed to confirm the last finding. “In the era of interferon, patients with advanced cirrhosis and fibrosis who achieved SVR [sustained virologic response] also experienced some important clinical end points in long-term follow-up: reduction in liver-related death and all-cause mortality, reduced hepatocellular carcinoma and reduced risk for liver decompensation and need for transplant,” said Gregory Everson, MD, professor of medicine at the University of Colorado School of Medicine, in Denver.

platelet count of at least 60,000, serum albumin of at least 2.8 g/dL and total bilirubin below 3 mg/dL. “This allowed for inclusion of sicker patients,” Dr. Everson said. The results “were really quite spectacular,” Dr. Everson said. SVR12 was achieved in 91.8% in the 12-week arm and 96.5% in the 24-week arm. Two percent discontinued the study as a result of adverse events, according to the researchers. “With such high SVRs, we could

really look at the impact of this treatment on the liver,” Dr. Everson said. As part of the study, Dr. Everson and his colleagues evaluated liver injury by assessing changes in alanine transaminase, aspartate aminotransferase and γγ-glutamyl transpeptidase. They also assessed liver function by measuring the change in bilirubin, albumin and prothrombin time, and portal circulation by monitoring platelet count. “As expected with viral clearance, 70% and 90% of

‘There are no other disease states where we can replicate such high cure rates. This has expanded logarithmically our ability to cure people. The concept that we can cure the vast majority of the cirrhotic patients we treat is just transformative.’ —David Bernstein, MD, FACG

“That was great, but interferon was not tolerated well by this population, and the rates of SVR were low. Now that we have interferon-free treatments, we hope to see a greater number of patients experiencing these benefits.” The TURQUOISE II trial (N Engl J Medd 2014;370:1973-1982), the first Phase III, randomized controlled trial to study the effects of a three direct antiviral (3D) regimen in cirrhotic patients with hepatitis C virus (HCV; genotypes 1a and 1b), randomized 380 patients to 12 weeks (n=208) or 24 weeks (n=172) of ABT-450/r (low-dose ritonavir)/ombitasvir and dasabuvir plus ribavirin (RBV). The final end point was SVR12; patients were followed for 48 weeks. Treatment-naive patients and those who had previously received peg interferon plus RBV were included in the trial. Patients were eligible if they had a

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patients normalized the liver enzymes in post-treatment follow-up,” Dr. Everson said. More importantly, the researchers found improvements in liver function, defined as a reduction in conjugated bilirubin and increased serum albumin. About 90% of patients with prior abnormalities in bilirubin achieved normalization. Similar findings were seen with albumin levels, the researchers said. see Sickest, page 36

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

Survey Shows Adoption of NAFLD Treatment Guidelines Varies Widely BOSTON—Gastroenterologists and hepatologists are inconsistently following many of the recommendations from clinical guidelines for nonalcoholic fatty liver disease (NAFLD), according to a national survey of physicians in the United States. The results showed that adherence rates ranged from 40% for some recommendations to close to 100% for others. “The adherence rates aren’t significantly lower than what is seen for other clinical guidelines, but adherence is less than ideal, particularly with respect to selection of patients for treatment,” said Mary Rinella, MD, associate professor of medicine at Northwestern University Feinberg School of Medicine, in Chicago, who helped lead the survey. Dr. Rinella’s group presented the results at the 2014 Liver Meeting of the American Association for the Study of Liver Diseases (AASLD; poster 838). Naga Chalasani, MD, a senior author of the NAFLD guidelines, said he was not surprised by the survey results because many of the pharmacologic treatment recommendations were not compelling, but were based on evolving and limited evidence rather than extensive published data. Furthermore, he added, the guidelines were only recently released. “Fundamentally, the guidelines are only a couple of years old. Clinicians don’t just read the guidelines and change their practice immediately,” Dr. Chalasani, director of the Division of Gastroenterology and Hepatology at Indiana University, in Indianapolis, told Gastroenterology & Endoscopy News. Three leading American gastroenterology societies— the American Gastroenterological Association, AASLD and the American College of Gastroenterology—created the NAFLD guidelines. The document was published simultaneously in 2012 in Gastroenterology, Hepatology and the American Journal of Gastroenterology. The 23-question survey developed by Dr. Rinella and

Table 2. Annual Number of Patients Wth NAFLD or NASH Referred For Bariatric Surgery

her colleagues collected information about respondents’ practice environments; the use of invasive and noninvasive diagnostic techniques; beliefs about the roles of diet, exercise and selected medications in the treatment of NAFLD; and the frequency of referral for bariatric surgery. Of the 482 clinicians surveyed, 163 responded. Respondents were predominantly academic hepatologists (57%), followed by academic clinicians in gastroenterology and hepatology (39%), private practice gastroenterologists and hepatologists (3%) and private practice hepatologists (1%). Although more than 95% of clinicians followed recommendations pertaining to diet and exercise, they were less adherent to those involving diagnosis and treatment, according to the researchers. Dr. Rinella said she was particularly concerned about the percentage of clinicians who treat patients with vitamin E or pioglitazone without first confirming nonalcoholic steatohepatitis (NASH) with a biopsy (Table 1). The guidelines strongly recommend a biopsy to confirm NASH, the most severe form of NAFLD, before treatment with drugs. Only 42% of general gastroenterologists and 47% of hepatologists said they required biopsy-confirmed NASH before starting therapy with vitamin E. Only 59% of gastroenterologists and 73% of hepatologists said they required biopsy-confirmed NASH before starting treatment with pioglitazone. “I was expecting the academic hepatologists to be much more adherent to treatment recommendations than gastroenterologists who don’t exclusively care for patients with liver disease,” Dr. Rinella said. “Since biopsy remains the only reliable method to diagnose NASH, I was surprised that so many treated patients that are unlikely to derive significant benefit from pharmacologic therapy.” Clinicians should not recommend treatment with either vitamin E or pioglitazone without a diagnosis

Number of Referrals

GastroenterologistsHepatologists, %

Hepatologists, %

34.8

1-5

62.8

10.6

14.9

>10

4.5

5.3

NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis

because both can cause side effects and there is no clear benefit to patients with non-NASH fatty liver, Dr. Rinella added. Vitamin E has a small risk for bleeding, cardiovascular problems and prostate cancer. Pioglitazone may cause side effects such as weight gain, worsening heart failure and bladder cancer. Dr. Rinella said she also was surprised to see the low rates of referral for bariatric surgery (Table 2). “Clinicians do not tend to send obese patients with NASH to bariatric surgery as often as they probably should,” Dr. Rinella said. “There are survival benefits from bariatric surgery in patients meeting criteria. It is a very effective modality for weight loss, and available data suggests it may be more effective than any drug that we have yet to improve NASH and its associated comorbidities.” Dr. Chalasani pointed out that the field of NAFLD is still not mature. “Our understanding of disease staging and pharmacotherapy is rapidly evolving. The survey results highlight these uncertainties and knowledge gaps,” he said. “There are a lot of unanswered questions. The guidelines made some recommendations that are helpful to practicing clinicians, but more clinical research is needed to make recommendations that are strong and supported by high-quality evidence.” —Kate O’Rourke Drs. Rinella and Chalasani reported no relevant financial conflicts of interest.

Table 1. Sample of Survey Questions Question

GuidelineGastroenterologist-Hepatologists Based Answer Adherent to Guideline, %

Hepatologists Adherent To Guideline, %

If you use vitamin E, do you require biopsy-confirmed NASH before starting therapy?

Yes

If you use pioglitazone, do you require biopsy-confirmed NASH before starting therapy?

Yes

Do you recommend bariatric surgery for patients with compensated NASH cirrhosis?

Yes

Are elevated liver enzymes required for you to consider liver biopsy in patients with fatty liver identified on imaging?

NASH, nonalcoholic steatohepatitis

Sickest continued from page 35

Some patients experienced an increase in platelet counts, suggesting less splenic sequestration of platelets due to reduction in portal hypertension. A significant increase in platelet count was achieved only in the 24-week group, suggesting that improvement in portal circulation may take a longer period of follow-up, said Dr. Everson, who presented the findings

at the 2014 meeting of the American College of Gastroenterology (abstract 5). “To me, the most important part of this study is not that their liver enzymes are corrected, but that these patients with cirrhosis are experiencing a 92% to 96% cure rate,” David Bernstein, MD, FACG, director of the Center for Liver Disease at the North Shore LIJ Health System, in Manhasset, N.Y., told Gastroenterology & Endoscopy News.

The proportion of cirrhotic HCV patients to achieve SVR with the oral, interferon-free regimen is almost as high as it is for non-cirrhotic HCV patients, of whom about 98% achieve SVR, said Dr. Berntein, who was not involved in the study. “We were pleasantly surprised, as the results we’re seeing are revolutionary. There are no other disease states where we can replicate such high cure rates,” Dr.

Bernstein said. “This has expanded logarithmically our ability to cure people. The concept that we can cure the vast majority of the cirrhotic patients we treat is just transformative.” —Monica J. Smith The study was supported by AbbVie. Dr. Everson and other authors receive research/ grant support from AbbVie and other companies. Dr. Bernstein receives research/grant support from AbbVie and other companies.

Now, less is an option.

GaviLyt y e-H Introducing GaviLyte™-H • Compare to HalfLytely®* • Now available as a generic • 2 liters and 1 Bisacodyl tablet

Now, patients, prescribers and pharmacists have a choice – with GaviLyte-H. This 2-liter volume PEG-3350 with bisacodyl tablet provides an alternative pre-colonoscopy prep and is now available as a value-branded generic. GaviLyte-H is part of our complete family of generic PEG-3350 products, and is just one more example of how GAVIS Pharmaceuticals is listening – and delivering – what patients, physicians and pharmacists want: a choice. Learn more at gavilyte.com. *HalfLytely is a registered trademark of Braintree Laboratories, Inc.

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

IBD Status Not Linked to Poor Labor Outcomes PHILADELPHIA— —Women with inflammatory bowel disease (IBD) are increasingly favoring cesarean over vaginal delivery, but new research suggests the disease need not dictate their decisions about childbirth. “The growing body of literature provides reassurance about the impact of IBD and IBD treatments on pregnancy outcomes, but there was little objective data to address concerns about the mode of childbirth and its impact on disease,” said Ashwin N. Ananthakrishnan, MD, MPH, assistant professor of medicine at Massachusetts General Hospital, in Boston. “We wanted to examine the impact of mode of delivery on the risk for new perianal disease in women with IBD, and on long-term outcomes including the need for therapy escalation and abdominal surgery,” he said. Dr. Ananthakrishnan and his colleagues identified 360 women with IBD who had experienced at least one pregnancy and childbirth, considering age at pregnancy, age at first diagnosis of IBD, disease

duration, type of IBD, complicated disease phenotype and IBD medications. The researchers excluded women whose first diagnosis of IBD occurred after pregnancy and those who experienced spontaneous abortion, and limited the study population to the first pregnancy with IBD. The study’s primary outcomes were perianal disease and related complications, defined as a new diagnosis of perianal fistula or abscess or perianal surgery in the four years after delivery. The researchers also looked for incidences of surgery related to IBD and the initiation of immunomodulators or anti–tumor necrosis factor therapy. The study population included 199 women who had a vaginal delivery and 161 who had cesarean delivery. Women in the latter group tended to be slightly older, to have preexisting perianal disease and, in those with Crohn’s disease, to have strictures or fistulae. “We also saw that women who delivered by C-section were more likely to have had

an IBD-related surgery previously,” Dr. Ananthakrishnan said. Among the 133 patients with Crohn’s disease and no prior perianal disease, 10 received a new diagnosis of perianal disease, a slightly higher frequency than in the other group. The difference reflects “the greater severity of disease in this population,” Dr. Ananthakrishnan said, although it did not persist on multivariate analysis. New diagnoses of perianal disease were about as common for women who underwent either mode of childbirth. “Looking at harder outcomes, like perianal disease– related surgery, the numbers were very similar. There were also no significant differences in perianal disease complications following delivery, or IBD-related hospitalizations, surgeries or therapy escalation,” Dr. Ananthakrishnan said. “Further studies are needed, but this provides reassurance to women contemplating vaginal delivery that it is certainly safe,” he said.

Sunanda Kane, MD, professor of medicine at Mayo Clinic, in Rochester, Minn., welcomed the new data. “It was about time someone updated the single study from 1996 we kept citing,” she said. “Perhaps the most interesting finding of this study was that the rate of C-section was 45%, which is quite high,” Dr. Kane said. Dr. Kane noted that the old literature suggested a 17% risk for developing perianal disease after vaginal delivery, “but now, with more effective therapies, we are likely healing mucosa at a higher rate,” she said. “Women with IBD are not immune to other birth-related morbidities, such as pelvic floor weakness, as they get older, but to know that a vaginal birth does not hasten unfavorable disease outcomes is reassuring.” The research was presented at the 2014 annual meeting of the American College of Gastroenterology (abstract 58). —Monica J. Smith

Primary Tumor Resection in CRC May Be Overused

rimary tumor resection may be performed too frequently for patients with advanced colorectal cancer (CRC) in the United States, according to a new study. According to a report published online in JAMA Surgery, patients with stage IV CRC are undergoing primary tumor resection (PTR) less often since 1998, with a marked drop-off after 2001 as new chemotherapeutic and biologic agents became available. By 2010, the last year of data analyzed, 57.4% of patients underwent PTR, down from 74.5% in 1988, the study found. However, the investigators said that despite the decrease, those figures indicate many patients may be undergoing surgery for CRC needlessly.

“It appears that current treatment practice may still lag behind evidence-based treatment guidelines and that there is still work needed to translate evidence on the effectiveness of health care decisions into clinical practice,” researchers at the University of Texas MD Anderson Cancer Center, in Houston, reported. Current guidelines from the National Comprehensive Cancer Network recommend systemic chemotherapy without PTR in patients presenting with non-obstructive unresectable stage IV disease. However, questions persist about the potential benefits and harms of PTR in the absence of symptoms. Many physicians and patients are concerned that patients whose primary tumors are asymptomatic may develop symptoms such as obstruction and bleeding on chemotherapy, said senior author George Chang, MD, associate professor of surgical oncology and health services research at MD Anderson, in a statement. “We know from a previous Phase II, cooperative group study that it’s safe to give chemotherapy even with biologics to patients with metastatic disease. Yet, there’s still controversy about the role of primary tumor resection because some believe there’s a survival association.” For the retrospective, population-based study, Dr. Chang and his colleagues used the National Cancer Institute’s (NCI) Surveillance, Epidemiology, and End Results (SEER) program database to identify 64,157 patients, all of whom were diagnosed with metastatic colon or rectal cancer between Jan. 1, 1988 and Dec. 31, 2013. Overall, 67.4% of patients underwent PTR, with those receiving the surgery more likely to be female, younger than 50 years old, married, and to have colon cancer and a high-grade tumor. Independent of receiving PTR, the researchers also found that the median relative survival rate of metastatic colon cancer patients improved from 8.6% in 1988 to 17.8% in 2009. Dr. Chang said he hoped the findings might help

patients and physicians make decisions about the need for PTR in the metastatic setting. Christopher Mantyh, MD, chief of colorectal surgery at Duke University Medical Center, in Durham, N.C., agreed that PTR may be overused in the United States, but highlighted the need for more research. “I agree with the conclusion that we probably do overuse primary tumor resection in someone who is nonsymptomatic from their cancer and has really truly unresectable disease,” said Dr. Mantyh, who was not involved with the study. He said the study’s strength and its weakness is that the conclusions are based on analysis of the SEER database. “Obviously, it’s a huge database, but it only represents 20% of patients in the country, so clearly there can be a selection bias.” Moreover, SEER does not include important details on issues such as individual patient factors and institutional factors that can affect the decision to use or not to use PTR, Dr. Mantyh noted. The study did not directly compare survival between patients who received and did not receive PTR, as SEER data make such evaluation impossible without significant risk for bias. The researchers also lacked information about systemic chemotherapy. A large randomized trial is currently underway in Europe that will examine the issue of PTR and survival. It is not known when results from this trial will be available. Beyond the current primary indication for PTR, Dr. Chang said there may be a group of patients for whom PTR may be beneficial because it may allow them to continue to receive chemotherapy. In the general population of metastatic CRC patients for whom resection cannot be performed, PTR can result in unanticipated delays or inability to receive systemic therapies. —Christina Frangou

Albert Einstein used with permission of the HUJ/GreenLight.

INDICATION HARVONI is indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection in adults.

Please see Brief Summary of full Prescribing Information adjacent to this ad.

HARVONI is the only HCV treatment offering an 8-week course of therapy1 % SVR12 among treatment-naïve HCV GT 1 subjects without cirrhosis who had baseline HCV RNA <6 million IU/mL1

100 90 Percent (%) Subjects

97%

70 60 50 40 30 20 10 0

n=119/123

HARVONI 8 weeks ION-3

• Overall SVR12 was 94% (n=202/215) in subjects receiving HARVONI for 8 weeks1,a • In treatment-naïve subjects taking HARVONI for 12 weeks, 96% (n=208/216) achieved SVR12 in the ION-3 trial and 99% (n=210/213) achieved SVR12 in the ION-1 trial1,a • The recommended treatment duration for treatment-naïve patients is 12 weeks1 • HARVONI for 8 weeks can be considered in treatment-naïve patients without cirrhosis who have pre-treatment HCV RNA <6 million IU/mL1 Study Designs ION-11: a randomized, open-label trial evaluating HARVONI with or without ribavirin (RBV) in GT 1 treatment-naïve subjects (N=865) with or without cirrhosis. Subjects were randomized in a 1:1:1:1 ratio to receive HARVONI for 12 weeks, HARVONI + RBV for 12 weeks, HARVONI for 24 weeks, or HARVONI + RBV for 24 weeks, and stratifi fied by presence or absence of cirrhosis and HCV genotype (1a vs 1b). ION-31: a randomized, open-label trial in GT 1 treatment-naïve subjects (N=647) without cirrhosis. Subjects were randomized in a 1:1:1 ratio to receive HARVONI for 8 weeks, HARVONI + RBV for 8 weeks, or HARVONI for 12 weeks, and stratified fi by HCV genotype (1a vs 1b). a SVR12 was the primary endpoint and was defined fi as HCV RNA <25 IU/mL at 12 weeks after the end of treatment.1 Achieving SVR is considered a virologic cure.2 RBV was not shown to increase the response rates observed with HARVONI in ION-1 or ION-3. Therefore, the HARVONI + RBV arms are not presented.1

IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS • Risk of Serious Symptomatic Bradycardia when Coadministered with Amiodarone: Amiodarone is not recommended for use with HARVONI due to the risk of symptomatic bradycardia, particularly in patients also taking beta blockers or with underlying cardiac comorbidities and/or with advanced liver disease. In patients without alternative, viable treatment options, cardiac monitoring is recommended. Patients should seek immediate medical evaluation if they develop signs or symptoms of bradycardia. • Risk of Reduced Therapeutic Eff ffect of HARVONI Due to P-gp Inducers: Rifampin and St. John’s wort are not recommended for use with HARVONI as they may signiﬁ ﬁcantly decrease ledipasvir and sofosbuvir plasma concentrations. • Related Products Not Recommended: HARVONI is not recommended for use with other products containing sofosbuvir (SOVALDI®).

HARVONI is the only once-daily single-tablet regimen for HCV GT 1 patients1

Recommended treatment duration1

HARVONI TABLET ONCE DAILY WITH OR WITHOUT FOOD

Can be considered in treatmentnaïve patients without cirrhosis who have pre-treatment HCV RNA <6 million IU/mL

weeks

Treatment-naïve patients with or without cirrhosis

Treatment-experienced patientsb without cirrhosis

weeks

Treatment-experienced patientsb with cirrhosis

weeks

Treatment-experienced patients who failed treatment with either peginterferon (Peg-IFN) alfa + ribavirin (RBV) or an HCV protease inhibitor + Peg-IFN + RBV.1

• HARVONI is interferon- and RBV-free for GT 1 treatment-naïve and treatment-experienced patients with or without cirrhosis, regardless of GT 1a or 1b subtype1 • Each HARVONI tablet contains 90 mg of ledipasvir and 400 mg of sofosbuvir1 • Relapse rates are aff ffected by baseline host and viral factors and diff ffer between treatment 1 durations for certain subgroups • No dose adjustments are required based on advanced age, mild or moderate renal impairment, or mild, moderate, or severe hepatic impairment. The safety and effi fficacy of HARVONI have 1 not been established in patients with decompensated cirrhosis • No dose recommendations can be given for patients with severe renal impairment (estimated glomerular ﬁ ﬁltration rate [eGFR] <30 mL/min/1.73m2) or with end stage renal disease (ESRD) due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite1

IMPORTANT SAFETY INFORMATION ADVERSE REACTIONS Most common (≥10%, all grades) adverse reactions were fatigue and headache.

DRUG INTERACTIONS • In addition to rifampin and St. John’s wort, coadministration of HARVONI is also not recommended with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifapentine, and tipranavir/ritonavir. Such coadministration is expected to decrease the concentration of ledipasvir and sofosbuvir, reducing the therapeutic effect ff of HARVONI. • Coadministration of HARVONI is not recommended with simeprevir due to increased concentrations of ledipasvir and simeprevir. Coadministration is also not recommended with rosuvastatin or co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate due to increased concentrations of rosuvastatin and tenofovir, respectively. Consult the full Prescribing Information for HARVONI for more information on potentially signiﬁcant ﬁ drug interactions, including clinical comments. Please see Brief Summary of full Prescribing Information on the following pages.

Visit harvoni.com/hcp

HARVONI® (ledipasvir 90 mg and sofosbuvir 400 mg) tablets, for oral use Brief Summary of full Prescribing Information. See full Prescribing Information. Rx Only. INDICATIONS AND USAGE: HARVONI is indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection in adults. CONTRAINDICATIONS: None WARNINGS AND PRECAUTIONS: Serious Symptomatic Bradycardia When Coadministered with Amiodarone: Postmarketing cases of symptomatic bradycardia, as well as fatal cardiac arrest and cases requiring pacemaker intervention, have been reported when amiodarone is coadministered with HARVONI. Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment. Patients also taking beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this effect is unknown. Coadministration of amiodarone with HARVONI is not recommended. For patients taking amiodarone who will be coadministered HARVONI and patients taking HARVONI who need to start amiodarone, who have no other alternative, viable treatment options; and due to amiodarone’s long half-life for patients discontinuing amiodarone just prior to starting HARVONI: Counsel patients about the risk of serious symptomatic bradycardia; and cardiac monitoring in an in-patient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment. Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion or memory problems. Risk of Reduced Therapeutic Effect Due to P-gp Inducers: Concomitant use may significantly decrease ledipasvir and sofosbuvir concentrations and may lead to a reduced HARVONI effect. Use of HARVONI with P-gp inducers (e.g., rifampin or St. John’s wort) is not recommended. Related Products Not Recommended: Use of HARVONI with products containing sofosbuvir (SOVALDI®) is not recommended. ADVERSE REACTIONS: The safety assessment of HARVONI was based on pooled data from three Phase 3 clinical trials in subjects with genotype 1 CHC with compensated liver disease (with and without cirrhosis) who received HARVONI for 8 (N=215), 12 (N=539) and 24 (N=326) weeks. Adverse events led to permanent treatment discontinuation in 0%, <1% and 1% of subjects receiving HARVONI for 8, 12 and 24 weeks, respectively. Adverse Reactions (adverse events assessed as causally related by the investigator): The most common adverse reactions (≥10%; all grades) were fatigue and headache. Adverse reactions (all grades; majority Grade 1) observed in ≥5% of subjects by treatment duration were:

• HARVONI for 8 weeks: fatigue (16%); headache (11%); nausea (6%); diarrhea (4%); and insomnia (3%) • HARVONI for 12 weeks: fatigue (13%); headache (14%); nausea (7%); diarrhea (3%); and insomnia (5%) • HARVONI for 24 weeks: fatigue (18%); headache (17%); nausea (9%); diarrhea (7%); and insomnia (6%) Direct comparison across trials should not be made due to differing trial designs. Laboratory Abnormalities: Bilirubin Elevations: Bilirubin elevations of greater than 1.5x ULN were observed in 3%, <1% and 2% of subjects treated with HARVONI for 8, 12 and 24 weeks, respectively. Lipase p Elevations: Transient, asymptomatic lipase elevations of greater than 3x ULN were observed in <1%, 2% and 3% of subjects treated with HARVONI for 8, 12 and 24 weeks, respectively. Creatine Kinase: Creatine kinase was not assessed in Phase 3 trials of HARVONI. Isolated, asymptomatic creatine kinase elevations (Grade 3 or 4) have been previously reported in subjects treated with sofosbuvir in combination with ribavirin or peginterferon/ribavirin in other clinical trials. Postmarketing Experience Cardiac Disorders: Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with HARVONI during post approval use of HARVONI. Because postmarketing 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. DRUG INTERACTIONS: Ledipasvir is an inhibitor of the drug transporters P-gp and breast cancer resistance protein (BCRP) and may increase intestinal absorption of coadministered substrates for these transporters. Ledipasvir and sofosbuvir are substrates of P-gp and BCRP while the inactive sofosbuvir metabolite GS-331007 is not. P-gp inducers (e.g. rifampin or St. John’s wort) may decrease ledipasvir and sofosbuvir concentrations leading to reduced HARVONI effect; use of HARVONI with P-gp inducers is not recommended. Established and Potentially Significant Drug Interactions: The drug interactions described are based on studies conducted in healthy adults with either HARVONI, the components of HARVONI as individual agents, or are predicted drug interactions that may occur with HARVONI. This list includes potentially significant interactions but is not all inclusive. An alteration in dose or regimen may be recommended for the following drugs when coadministered with HARVONI: • Acid Reducing Agents: Ledipasvir solubility decreases as pH increases. Drugs that increase gastric pH are expected to decrease ledipasvir concentration. • Antacids: Separate HARVONI and antacid administration by 4 hours. • H2-receptor antagonists: Doses comparable to famotidine 40 mg twice daily or lower may be administered simultaneously with or 12 hours apart from HARVONI. • Proton-pump inhibitors: Doses comparable to omeprazole 20 mg or lower can be administered simultaneously with HARVONI under fasted conditions.

Brief Summary (cont.)

USE IN SPECIFIC POPULATIONS:

• Antiarrhythmics (amiodarone; digoxin) Amiodarone: Coadministration of amiodarone with HARVONI may result in serious symptomatic bradycardia and is not recommended. Mechanism of effect is unknown. If coadministration is required, cardiac monitoring is recommended. Digoxin: Increased digoxin concentration. Monitor digoxin therapeutic concentration during coadministration with HARVONI.

Pregnancy: HARVONI is Pregnancy Category B; there are no adequate and well-controlled studies in pregnant women. HARVONI should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

• Anticonvulsants (carbamazepine; phenytoin; phenobarbital; oxcarbazepine): Decreased ledipasvir and sofosbuvir concentrations leading to reduced HARVONI effect. Coadministration is not recommended. • Antimycobacterials (rifabutin; rifampin; rifapentine): Decreased ledipasvir and sofosbuvir concentrations leading to reduced HARVONI effect. Coadministration is not recommended. • HIV Antiretrovirals • Regimens containing tenofovir disoproxil fumarate (DF) and an HIV protease inhibitor/ritonavir (emtricitabine/tenofovir DF plus atazanavir/ritonavir, darunavir/ritonavir or lopinavir/ ritonavir): The safety of increased tenofovir concentrations has not been established. Consider alternative HCV or antiretroviral therapy. If coadministration is necessary, monitor for tenofovirassociated adverse reactions. Refer to VIREAD or TRUVADA prescribing information for renal monitoring recommendations. • Efavirenz/emtricitabine/tenofovir DF: Monitor for tenofovirassociated adverse reactions. Refer to VIREAD, TRUVADA or ATRIPLA prescribing information for renal monitoring recommendations. • Elvitegravir/cobicistat/emtricitabine/tenofovir DF: The safety of increased tenofovir concentrations has not been established. Coadministration is not recommended. • Tipranavir/ritonavir: Decreased ledipasvir and sofosbuvir concentrations leading to reduced HARVONI effect. Coadministration is not recommended.

Nursing Mothers: Studies in rats have demonstrated that ledipasvir and GS-331007 are secreted in milk but had no effect on nursing pups. It is not known if HARVONI and its metabolites are secreted in human breast milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for HARVONI and any potential adverse effects on the nursing child from the drug or from the underlying maternal condition. Pediatric Use: Safety and effectiveness of HARVONI have not been established in pediatric patients. Geriatric Use: Clinical trials of HARVONI included 117 subjects aged 65 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. No dosage adjustment of HARVONI is warranted in geriatric patients. Renal Impairment: No dosage adjustment of HARVONI is required for patients with mild or moderate renal impairment. The safety and efficacy of HARVONI have not been established in patients with severe renal impairment (eGFR <30 mL/min/1.73m2) or end stage renal disease (ESRD) requiring hemodialysis. No dosage recommendation can be given for patients with severe renal impairment or ESRD. Hepatic Impairment: No dosage adjustment of HARVONI is required for patients with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B or C). Safety and efficacy of HARVONI have not been established in patients with decompensated cirrhosis.

• HCV Products (simeprevir): Increased ledipasvir and simeprevir concentrations. Coadministration is not recommended. • Herbal Supplements (St. John’s wort): Decreased ledipasvir and sofosbuvir concentrations. Coadministration is not recommended. • HMG-CoA Reductase Inhibitors (rosuvastatin): Significant increase in rosuvastatin concentrations and risk of rosuvastatin associated myopathy, including rhabdomyolysis. Coadministration is not recommended. Drugs without Clinically Significant Interactions with HARVONI: Based on drug interaction studies conducted with HARVONI or its components, no clinically significant drug interactions have been observed or are expected when used with the following drugs individually: abacavir, atazanavir/ritonavir, cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, lamivudine, methadone, oral contraceptives, pravastatin, raltegravir, rilpivirine, tacrolimus, tenofovir DF or verapamil. Consult the full Prescribing Information prior to and during treatment with HARVONI for potential drug interactions; this list is not all inclusive.

References: 1. HARVONI US full Prescribing Information. Gilead Sciences, Inc. Foster City, CA. March 2015. 2. US Department of Health and Human Services, Center for Drug Evaluation and Research. Draft Guidance for Industry. Chronic Hepatitis C Virus Infection: Developing Direct-Acting Antiviral Drugs for Treatment. October 2013.

HARVONI, the HARVONI logo, SOVALDI, TRUVADA, VIREAD, GILEAD and the GILEAD logo are trademarks of Gilead Sciences, Inc., or its related companies. ATRIPLA is a trademark of Bristol-Myers Squibb & Gilead Sciences, LLC. ©2015 Gilead Sciences, Inc. All rights reserved. HVNP0241 04/15

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

Colorectal 2015: Dueling Debates in Colorectal Surgery Participants Conor Delaney, MD, PhD, is chief of colorectal surgery and surgical director of the Digestive Health Institute at University Hospitals Case Medical Center, in Cleveland.

Jonathan Efron, MD, is interim director of the Department of Surgery, associate professor of surgery and urology, and Mark M. Ravitch MD endowed professorship of surgery, at Johns Hopkins University, in Baltimore.

his On the Spott presents several of the most current debates in colorectal surgery. Special thanks to Dr. Steven Wexner for lending his expertise and thoughts on each topic. Read on, take a side! —Colleen Hutchinson Editor’s note: A version of this article first appeared in General Surgery News.

Abe Fingerhut, MD, FACS, FRCPS (g), FRCS (Ed), (Hon c.), is professor of surgery at the University of Graz, in Austria.

Statement: Transanal total mesorectal excision (TaTME) for rectal cancer offers superior

Stephen R. Gorfine, MD, is clinical professor of surgery at the Icahn School of Medicine at Mount Sinai, and attending surgeon in the Division of Colon and Rectal Surgery at Mount Sinai Hospital, in New York City. Antonio Lacy, MD, is chief of the Gastrointestinal Surgery Department, and professor of surgery at the University of Barcelona School of Medicine, in Spain.

Jorge Lagares-Garcia, MD, is chair of the Division of Colon and Rectal Surgery at Roper Hospital, in Charleston, S.C. Disclosure: Dr. Lagares-Garcia is instructor and consultant for Intuitive Surgical. Feza H. Remzi, MD, is chairman of the Department of Colorectal Surgery at Cleveland Clinic, in Ohio.

Steven Wexner, MD, is director of the Digestive Disease Center and chairman of the Department of Colorectal Surgery at Cleveland Clinic Florida, in Weston. Disclosure: Dr. Wexner reported stock options from past consulting with Intuitive Surgical, and consulting fees and inventor’s income from Karl Storz. Oded Zmora, MD, is director of colon and rectal surgery at Sheba Medical Center, in Tel Aviv, Israel.

oncologic outcomes as compared to standard transabdominal TME.

Conor Delaney, MD: Disagree. TaTME is an interesting new extension of an old technique, but there are as yet no data supporting superior oncologic outcomes. Remember, intersphincteric resection has been around for a long time for the tumors within 1 cm of the dentate line, and many surgeons do a transanal mobilization of the distal rectum for lowerthird rectal tumors, especially when approached laparoscopically. These appear to be equivalent to a standard transabdominal approach (whether open or laparoscopic). In fact, in a systematic review we recently published in Surgical Endoscopy, 11.8% of TaTME circumferential margins were positive, and pneumo-retroperitoneum, air embolism and urethral injury had been reported, despite TaTME generally being done to date by very experienced surgeons. Although TaTME may help reduce the conversion rate for laparoscopic surgery for low rectal tumors in obese males, we must be careful that we do not trade this for worse oncologic outcomes and higher complication and injury rates. TaTME is likely to be oncologically equivalent, and must be evaluated to make sure it is so, but we need more data before saying it is better.

Antonio Lacy, MD: Agree. Recently, some studies have shown the feasibility of TaTME, and some comparative studies have been published showing that it is not inferior to standard transabdominal TME in terms of short-term outcomes. These outcomes also stand for surgical-related aspects that may have

future impact on disease recurrence, such as better measure of distance from the anal verge or circumferential resection margin (CRM). And last year, a randomized study concluded that, for low rectal cancer, TaTME reduced the risk for positivity of that margin. And what to say about differences in distal margin! Nowadays, everybody looks forward to oncologic long-term outcomes. We all know that randomized controlled trials are warranted; however, existing data seem to be promising, suggesting a tendency to improve disease-free survival after TaTME. These questions will be answered in the near future, but as an experienced rectal surgeon, I strongly believe that a quality surgery may offer superior long-term oncologic outcomes.

Dr. Wexner weighs in: TaTME is a very promising new technology that seems to result in equivalent—and may, in fact, ultimately be proven to offer superior— oncologic outcomes to transabdominal TME. Moreover, part of the tremendous appeal of TaTME is the ability to avoid the expense of the robotic platform to “facilitate” the distal pelvic dissection. Virtually every study during the past nearly 25 years has shown numerous significant short-term benefits comparing laparoscopic to open TME relative to pain, length of hospitalization, length of cosmetic outcomes, length of ileus and other variables. Additionally, a myriad of authors have demonstrated oncologic superiority relative to lymph node harvest and/or tumor-free margins. Although robotic TME has failed to confer any proven advantage as compared with laparoscopic TME, many individuals market this approach as a way to flatten, shorten or eliminate the learning curve to transition from open to minimally invasive transabdominal TME. TaTME is appealing in that it offers the possibility to eliminate the costly cumbersome robotic platform while conveying equivalent or perhaps even superior oncologic outcomes. Therefore, although TaTME has not yet been proven to

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

offer superior oncologic outcomes compared with standard transabdominal TME, it does certainly offer promise in this direction.

Statement: Bowel preparation is mandatory for elective colorectal surgery.

Abe Fingerhut, MD: Agree. Mechanical bowel preparation (MBP) before elective colorectal surgery—a timehonored dogma—is thought to decrease the intraluminal fecal mass and, presumably, also the bacterial load in the bowel, in turn reducing the postoperative infectious complication rate (including anastomotic leakage and surgical site infection). Challenged by trauma surgeons when primary repair of colonic injury provided good results (Br J Surgg 2007;94:689-695) several studies have since contested this idea; one of the most recent systemic reviews and meta-analysis does not support the routine use of MBP before colonic cancer surgery in terms of reduction of infectious postoperative complications (Lancett 2007;370:2112-2117). However, the impact of MBP is still unclear in rectal surgery because many studies in the literature excluded rectal surgery, and only one French multicenter randomized trial has demonstrated that rectal surgery without MBP is associated with higher risk for overall and infectious morbidity rates, suggesting continuing to perform MBP before elective rectal resection (Cochrane Database Syst Rev v 2011:CD001544). Because laparoscopy may pose specific difficulties in localization of small, nonpalpable lesions without serosal surface la ndmarks, bowel preparation should still be considered because of the need for intraoperative colonoscopy in this setting. In conclusion, there is no strong evidence suggesting the routine use of MBP for elective colonic resection. However, preoperative MBP may be recommended in selected patients with intraperitoneal rectal and/or small colorectal cancer in whom intraoperative colonoscopy might prove necessary for localization. This is especially important for patients undergoing laparoscopic surgery, where the surgeon’s ability to palpate the colon is limited.

one from the Netherlands with 1,260 patients) and a meta-analysis, all showed no advantage to MBP in terms of anastomotic leak, surgical site infection and postoperative complications. Scientific data are strong enough to support the omission of the routine use of MBP in elective colorectal surgery. It is time for a well-designed and well-performed North American study to convince most American surgeons, also. Special considerations that may selectively require MBP include small tumors that may need intraoperative endoscopy

“

for tumor localization, and perhaps rectal surgery. A single French randomized trial suggested a higher complication rate without preparation specifically in rectal surgery. These results should be reassessed in further studies. An interesting study was recently published by the Swedish multicenter group, suggesting that no bowel preparation may be associated with higher rate of cancer recurrence (Br J Surg 2014;101:1594-1600). The mechanism for this possible phenomenon, however, is poorly understood, and this should be further investigated in future studies.

Dr. Wexner weighs in: The main reason to perform bowel preparation for elective colorectal surgery is to facilitate bowel manipulation and intraoperative endoscopy. We have clearly demonstrated a lower incidence of postoperative anastomotic problems when routine intraoperative endoscopy is performed to assess pelvic anastomoses than when it is only selectively employed. Additionally, it may be necessary to perform endoscopy to visualize see Debate, page 47

AAAHC accreditation is testimony for your patients of your facility’s total commitment to quality care. Lawrence S. Kim, MD Gastroenterologist AAAHC Board Member

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Oded Zmora, MD: Strongly disagree. Numerous randomized prospective studies, including two large multicenter randomized prospective trials (one in Sweden with 1,343 patients and

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Debate continued from page 45

lesions, ink marks and bowel mucosa. Therefore, although routine MBP does not seem to be required for its originally stated purpose (to decrease or avoid surgical site infection), it has become a very useful adjunct to allow intraoperative endoscopic visualization, particularly during laparoscopic procedures. Also, the minimally invasive instrument manipulation of a fecally loaded colon seems less safe than is the handling of an empty colon.

Statement: Routine one-stage (as opposed to two-stage) restorative proctocolectomy is recommended.

Feza Remzi, MD: Disagree. I do believe patients who undergo restorative proctocolectomy (RPC) have the best outcome when all goes well at the initial surgery. Personally, by doing a routine one-stage RPC, we are taking an unnecessary risk on behalf of our patients, especially in patients with inflammatory bowel disease (IBD). This was a controversial topic to start with in the prebiologic era. Some did it routinely; some, like our group, did it selectively, depending on the preoperative and intraoperative stringent criteria. We are in the biologic era in which almost no patient with IBD is referred to surgery without the trial of biologics. These drugs are immunosuppressant to start with and there is a trend prolonging the treatment with biologics trying to avoid the unavoidable. These result in septic complications, which negatively affect the long-term outcomes. In my opinion, offering our patients a routine RPC in the biologic era is riskier than before. I do believe, unless it is a familial adenomatous patient who is motivated and fits to stringent criteria we employ, doing a one-stage RPC is an absolute contraindication in the biologic era.

Stephen Gorfine, MD: Disagree. One-stage RPC can be performed safely for a group of highly selected patients only. “Routine” use of this technique is not recommended. Temporary diversion in the setting of RPC does not prevent pouch or anastomotic leaks, but rather mitigates the consequences should one occur. One-stage RPC offers suitable patients the relative benefits of

elimination of the risks, discomfort and costs associated with a second surgery; reduced total hospital time; and complete avoidance of an ileostomy. These benefits must be weighed against the risk for potentially severe septic complications. Patients suitable for a one-stage RPC are generally taking less than 20 mg of prednisone daily and are not on multiple immunosuppressive medications such as infliximab in combination with cyclosporine and 6-mercaptopurine. Candidates for one-stage surgery are generally not overtly malnourished or “sick” with

an acute exacerbation of colitis. Surgery is always performed in the elective setting and must proceed smoothly. The ileal pouch–anal anastomosis (IPAA) must be completely tension-free. The final decision concerning omission of ileostomy is always made after the pouch and IPAA have been constructed. Using these criteria, we have successfully performed more than 400 onestage RPCs. Long-term functional results and complication rates are similar among patients undergoing RPC with and without diversion.

Dr. Wexner weighs in: Although one-stage pouches can be performed, I disagree that they should be done so routinely. The vast majority of studies and meta-analyses have decided in favor of two-stage J-pouches rather than one-stage J-pouches. Nonetheless, with careful patient selection, meticulous technique and a very well-informed patient, the procedure can, in selected cases, be undertaken. If after a lengthy informed consent, the patient still desires see Debate, page 48

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

Debate continued from page 47

a one-stage procedure and is a medically appropriate candidate (without significant malnutrition, taking less than 20 mg per day of prednisone, remote from any anti–tumor necrosis factor agents, and is not anemic or obese), then the surgeon must rely on the intraoperative decisionmaking algorithm. Only in instances of a “quick and easy” RPC with minimal blood loss and a tension-free anastomosis should avoidance of a temporary ileostomy be contemplated.

Statement: Robotic rectal cancer surgery has multiple proven advantages as compared to the laparoscopic

extremely low positive circumferential margin of 0.9% and 5.9% conversion rate independent of the patient’s BMI in 425 patients ((Ann Surg Oncoll 2014 Dec 9. [Epub ahead of print]). Local recurrence rate was 1.7%. Although the limitations of this study are clear in its retrospective nature, this large number of high-volume expert robotic surgeons clearly indicates the potential in rectal cancer surgery, although further randomized controlled trials, appropriately powered for each technique, are needed. In our current personal experience of more than 450 cases, in a nonteaching institution with a dedicated team, robotic proctectomy ranges from 120 to 150 minutes (unpublished data), clearly superior times to laparoscopic current series. Although the initial expense and cost is higher per case, the minimal conversion rate and the completion of the TME as a quality indicator in our current series is excellent.

approach. Jonathan Efron, MD: Disagree. Jorge Lagares-Garcia, MD: Agree. Laparoscopic TME has been proven to be safe, with lower morbidity and mortality. Despite that, the operative times and conversion rate are high, especially in patients with narrow pelvis or high body mass index (BMI). The robotic platform offers the surgeon an improved dexterity and vision in the performance of complex pelvic operations like rectal cancer. To date, the largest North American data of robotic rectal cancer recently published by Hellan et al showed comparable operative times than laparoscopic while offering an

Although I use the robot for rectal cancer surgery, there has yet to be any published data to support the statement: “Robotic rectal cancer surgery has multiple proven advantages as compared to the laparoscopic approach.” What I really disagree with in the statement is the word “proven.” I do feel the robot provides the added benefits of superior visualization, increased flexibility and greater ability to retract in the pelvis; those benefits have not been translated into proven advantages over the laparoscopic technique in any published trial. Multiple retrospective reviews have compared robotic to open, and robotic to laparoscopic proctectomy; the only advantage being proven to date is perhaps

a lower conversion rate with the robotic technique. To the detriment of the robot, its use clearly increases the length and the cost of minimally invasive proctectomies. To date, there is no good prospective trial demonstrating any benefit of the robotic technique over the laparoscopic technique. Hopefully, we will see some definitive data to either support or refute this statement in the near future as randomized trials comparing the two techniques are underway and near completion. For now, I am forced to disagree with the above statement.

Dr. Wexner weighs in: Within five years of the advent of laparoscopic colorectal surgery, a myriad of studies had demonstrated superior outcomes for pain, immunosuppression, length of ileus, ability to tolerate oral intake, resumption of bowel activity, hospital discharge, resumption of normal lifestyle, improved cosmesis, decreased adhesions, decreased ventral incisional hernia, decreased morbidity and decreased mortality. Within 10 years of the advent of laparoscopic colorectal surgery for rectal carcinoma, many more studies had already demonstrated either equivalent, or, in some cases, superior oncologic outcomes to laparotomy. Perhaps the most relevant study for robotics is the recent study by Park et al concluding that robotic rectal cancer surgery failed to confer any oncologic or other benefit [over standard laparoscopy]. In the study by Park et al, 217 patients who underwent minimally invasive surgery for rectal cancer were prospectively enrolled to undergo either robotic or laparoscopic rectal cancer surgery ((Ann Surgg 2015; 261:129-137). The authors concluded that “robotic surgery for rectal cancer failed

to offer any oncologic or clinical benefit compared with laparoscopy” despite a 2.34 times higher cost than laparoscopic surgery. I concur with this highly esteemed group of experienced robotic surgeoninvestigators. Moreover, the robotic platform is touted by its proponents and enthusiastically embraced by surgeons to “flatten” or “shorten” the “learning curve.” The reduced learning curve should therefore allow surgeons who do not frequently operate on rectal cancers to do so in a minimally invasive fashion. Although the short-term recovery benefits of the minimally invasive approach to the patients seem inherently obvious, unfortunately the long-term oncologic problems of lowvolume surgeons have been well demonstrated. Numerous studies have shown that rates of permanent colostomy and local recurrence are in inverse proportion to the volume of rectal cancer operations performed by individual surgeons and within individual institutions. Therefore, when robotic rectal cancer surgery is offered to patients by high-volume rectal cancer surgeons in high-volume rectal cancer centers, the oncologic outcomes are probably similar to the oncologic outcomes of either laparoscopy or open TME when performed by those same surgeons. However, sadly, the widespread advent of “easier” minimally invasive access may potentially allow lower-volume surgeons to operate on rectal cancer, which could possibly result in a higher incidence of use of permanent colostomy and a higher rate of local recurrence. Thus, the results of rectal cancer surgery are probably far less dependent on the method of access than on the expertise and commitment of the surgeon and the center at which the surgeon operates.

Table. Gut Reaction: Colorectal 2015 State of malpractice insurance in colorectal surgery

“Obamacare”

Best advice to the new medical Best advice to the community surgeon student who plans to specialwho would like to become more involved in ize in colorectal surgery colorectal surgery association leadership and general research/publication

The dynamic between oncologist and oncologic surgeon

Dr. Efron

The same as for the rest of surgery: poor.

Making significant changes.

Obtain the best training you can; it is the foundation for the future care you deliver.

Research and participation in a national society is dependent on the person, not their type of practice; if you enjoy either, you can do both.

A symbiotic relationship that partners to improve patient care.

Dr. Gorfine

Abysmal.

Worse than expected.

Great field; work hard and go for it!

Join the ASCRS and participate.

Often harmonious, sometimes testy.

Dr. Lacy

Not qualified to comment on the situation in the United States.

Work hard, take care of patients, study, then enjoy.

Surgery is essential, but innovation is too.

We work together in the committees and have a close relationship.

Dr. Lagares-Garcia

Really adequate?

“Equal access” must reflect “equal care.”

Best decision you ever will make. Join local societies and Web chats in ASCRS.

Needs improvement and a common goal.

Dr. Remzi

It is all over the place.

Let’s be part of the solution.

Best is yet to come; please join us.

Please tell us who you are.

We complete each other.

Dr. Zmora

Lose–lose situation.

Thank God I live in Israel.

Go for your dreams!

Multidisciplinary team: a win-win situation

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

Part 1 of a 2-Part Series

In-Hospital Malnutrition a Major Issue for Criticallly Ill LONG BEACH, CALIF.—Nourishment is essential to a functioning human body— especially when that body is battling illness or healing a wound. Why, then, is providing proper calories, protein and other nutrients so often overlooked in the care of a critically ill patient? A key barrier to such a seemingly obvious consideration, according to Phil Ayers, PharmD, chief of clinical pharmacy

services for Baptist Health Systems in Jackson, Miss., is the current lack of a gold standard for estimating caloric and protein needs in this population. Furthermore, health care providers lack the resources they need to ensure that the allotted nutrients reach the patient. Several abstracts presented at the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) annual

conference address these voids, underscoring the role that nutrition can play in hospital outcomes, and providing at least some hints of much-needed direction. Specifically, researchers suggested that worries about overfeeding obese patients might have been overblown. Of greater concern, they said, might be a situation in which a patient’s calorie or protein count has fallen too low.

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“If you don’t feed these people, especially if you don’t give them adequate protein, then wound healing is impaired, length of stay is longer, and morbidity and mortality rates are higher,” added Dr. Ayers, who was not involved in the studies. In-hospital feeding issues have been noted as far back as the 1970s, when Charles E. Butterworth Jr., MD, called it the “skeleton in the hospital closet” (Nutr Todayy 1974;9:4-8). The figures are stark. An estimated one in three Americans enter a hospital malnourished (Int J Environ Res Public Health 2011;8:514527). More patients, even many who arrive well nourished, tend to end up short on nutrition during their stay. Some deficits result by design, as studies in recent years suggested that reducing caloric goals might be optimal for certain patients’ health. In reality, those counts usually are further trimmed: Only 50% to 66% of prescribed calories and protein— whether or not the amounts are actually appropriate—are delivered to a patient, noted the researchers of a study presented at A.S.P.E.N. (abstract 4). The same team highlighted this dangerous inconsistency at last year’s conference (abstract 1). “If we didn’t complete a prescription for an antibiotic or blood pressure medicine, it would be unacceptable,” said Daniel (Dante) Yeh, MD, a trauma surgeon at Massachusetts General Hospital, in Boston, and the lead researcher of abstract 4. “But it’s pretty much routine for nutrition.” “Years ago, we were initially overfeeding,” added Carol Rollins, MS, RD, PharmD, a coordinator for the Nutrition Support Team at the University of Arizona Medical Center, in Tucson, who also was not involved in the abstracts. “Then I think we took a swing way over the edge with underfeeding; and now, we’re coming back to the middle—where we should be.”

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

magnified in the critically ill,” he added. “This presents a potential opportunity for improvement.” Complicating efforts to stave off malnutrition are the frequent interruptions to enteral nutrition faced by hospitalized patients. Last year at A.S.P.E.N., Dr. Yeh and his team estimated that nearly three-fourths of interruptions in surgical patients were unavoidable (abstract 1). He noted that it is imperative to “make up for lost time” by increasing nutrition before and after extubation, operations and other periods in which feeding is

not possible. Of course, this still leaves open the question of how many calories and how much protein is enough. The answer, whatever it may be, is far from one-size-fits-all. “The patient population that has us all somewhat stumped right now is the obese,” Dr. Rollins said.

Casting Doubt on Hypocaloric Goals Another pilot study presented at A.S.P.E.N. (abstract 10) sought to clarify the confusion regarding obesity and

caloric intake. Researchers randomized 83 surgical ICU patients to receive either their standard calculated daily caloric requirement (eucaloric) or half of that goal (hypocaloric). Protein targets were kept the same. They focused on the obese patients in the eucaloric and hypocaloric groups—11 and 19, respectively. What the researchers found surprised them. A total of 17 infections occurred among obese patients on the eucaloric diet compared with 58 infections among those receiving reduced calories. The see Malnutrition, page 52

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Malnutrition in incoming patients is generally out of the control of providers. “We are stuck with the hand we’ve been dealt,” Dr. Yeh said. “We can’t really exchange cards. But there are things we can do after they arrive.” For starters, the Joint Commission now requires that health care providers conduct a nutrition assessment when a patient enters a hospital. What providers do with that information is left up to them. The lack of guidance follows the lack of consensus on ideal calorie or protein counts among a diverse population of critically ill patients. “Nobody really knows” how much nutrition is needed, Dr. Yeh added. To that end, Dr. Yeh and his colleagues investigated the association between feeding in the hospital and a patient’s chances of being discharged home versus transferred to a rehabilitation or skilled nursing facility. They specifically looked at what he called a patient’s “cumulative debt” in terms of calories and protein. “Like the national debt, that number is always changing,” Dr. Yeh said. In the analysis of 213 patients admitted to the surgical ICU, they found that those whose cumulative caloric debt surpassed 6,000 kcal—based on their prescribed nutrition goals—were three times less likely to be discharged home than patients with deficits that did not reach that threshold (6% vs. 19%; P P=0.02). A similar difference appeared when they compared patients with protein deficits above and below 300 g (7% vs. 19%; P=0.02). The relationship remained P consistent after adjusting for body mass index and APACHE II scores. “Nutrition is required for every single process in the body—from fighting infection to proper functioning of the lungs and heart. You need those building blocks,” Dr. Yeh said. “The effects of malnutrition are

Malnutrition continued from page 51

mean number of infections per patient (1.5 vs. 3.1; P P=0.29) and the percentage of patients who acquired an infection (45.5% vs. 79%; P P=0.07), however, did not reach statistical significance. Furthermore, the two feeding protocols didn’t appear to influence weight gain differently. Added weight from fluid overload has been linked with worse outcomes in critically ill patients. The results “cast some doubt as to the appropriateness of broadly applying hypocaloric feeding to all critical care surgical patients,” said Eric Charles, MD, a surgeon with the University of Virginia Health System, in Charlottesvillle, and the lead researcher of the abstract. Based on the findings, Dr. Charles said his team will “continue to target full eucaloric goals.” He added that they have also discussed using volume-based feeding protocols to hit nutrition targets. Such strategies allow for the adjustment of the enteral feeding rate based on interruptions. Take, for example, an initial calorie-per-hour rate calculated by dividing a patient’s daily requirement by 20 hours to account for an estimated four hours of interruptions. Then if that patient’s feeding ends up interrupted for six hours of the day, the health care team can simply increase the hourly rate to make up the difference. Still, Dr. Charles emphasized that the bigger question remains unanswered. “We’re never really sure what the optimal caloric goal is or the optimal way to determine it,” he said. “Should it be based on body weight, a standard formula or something else?”

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

Specifically, among the study patients, it appeared to facilitate glucose control (average, 142.8 mg/dL) and nitrogen balance (seven patients had positive balance) without exceeding hypocaloric feeding goals. “We love it. It’s the highest proteinto-calorie formula that I know of, and is perfect for the at-risk obese patient,” said Andrew Bernard, MD, a surgeon at the University of Kentucky, in Lexington, who participated in the study, which Nestlé supported. “This addresses what’s long been a

challenge in nutrition,” Dr. Ayers added. “Although the study is small, it opens up opportunities for other researchers to create larger placebo-controlled trials looking at formulas with higher amounts of protein and lower calories.” Of course, as abstract 10 noted, whether or not obese patients should receive curtailed calorie counts remains unclear. “We have seen contradictory studies and statements,” Dr. Ayers said, noting that although the various studies presented at A.S.P.E.N. may be too

small and preliminary to change practice today, they help toward clarification and “create ideas and insight for further studies.” —Lynne Peeples Drs. Yeh, Rollins and Charles reported no relevant financial conflicts of interest. Dr. Ayers has served as a consultant for Baxter, B. Braun and Fresenius Kabi. Dr. Bernard is currently an investigator in a Nestlé-sponsored study.

Next issue: Part 2 will focus on tools for achieving adequate nutrient intake in critically ill children.

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Prioritizing Protein Also missing from providers’ toolkits, according to Dr. Ayers, has been a commercial formula appropriate for critically ill obese patients—one that contains adequate protein relative to a lower number of calories. Dr. Rollins agreed that researchers and health care practitioners “need to put more emphasis on protein.” A unique enteral formula designed to fill this void was highlighted in another pilot study presented at A.S.P.E.N. (abstract 12). The Nestlé Health Care Nutrition recipe—which contains 37% protein (100% whey hydrolysate), 31% carbohydrates, and medium-chain triglycerides, fish oil and prebiotic fiber—is currently available under the trade name “Peptamen Bariatric.” In a study of 16 critically ill obese patients who received enteral nutrition for at least three days, researchers found the high-protein, low-carbohydrate formula to be safe and well tolerated.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

Nutrition Deprivation Common in Hospitalized IBD Patients

any patients hospitalized with inflammatory bowel disease may be deprived of protein and calories critical to their health and recovery, researchers have found. Malnutrition in these patients can cause functional impairment and jeopardize tissue repair. It may also result in increased morbidity and mortality, decreased quality of life, higher health care costs, and longer and more frequent trips to the hospital.

The new study shows that more than half of patients hospitalized with IBD for at least five days became malnourished during their stay—despite the understanding among specialists that the need for adequate nutrition is critical during a bowel flare. “During a flare is when they need nutrition the most,” said Kimberly Kolkhorst, DO, a gastroenterologist at the University of South Florida, in Tampa, who led the study. Dr. Kolkhorst

and her colleagues presented their findings at the 2014 Advances in Inflammatory Bowel Diseases annual conference (abstract P-54). Patients with Crohn’s disease or ulcerative colitis already face the risk for malnutrition. Dr. Kolkhorst said that health care providers should avoid making the situation worse. Up to an estimated 85% of hospitalized patients with IBD may suffer from protein-calorie malnutrition, she added.

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The consequences of such untimely reductions in calories can include increased morbidity, mortality, hospital stays and health care costs. After noticing how frequently their hospital’s primary care teams would order patients with abdominal pain and nausea to discontinue consumption of any food or drink via mouth (NPO), Dr. Kolkhorst and her colleagues decided to investigate the rate of iatrogenic malnutrition in patients hospitalized with IBD. The team reviewed all inpatient gastroenterology consults to Tampa’s James A. Haley VA Hospital, between Jan. 1, 2013, and July 31, 2014, including records from hospital days 1 through 7 for patients with IBD. They defined iatrogenic malnutrition as patients with orders for NPO or a clear liquid diet for three or more days when hospitalized for at least five days. Of 71 patients with IBD, 34 (48%) were hospitalized for at least five days. The researchers found iatrogenic malnutrition in 18 of these patients (53%). “We thought it was going to be high but we didn’t think it would be that high,” Dr. Kolkhorst said, adding that her team is continually adding patients to increase the power of their study. “Clearly this is an issue that needs more attention.” Only four of the 18 patients should have been NPO because they required surgery, she said. “Optimal nutrition status should become part of the strategic quality care measures for hospitalized IBD patients,” Dr. Kolkhorst said. “Efforts need to be made to prevent overzealous NPO orders, lack of attention to diet orders, delayed endoscopies and delayed GI [gastroenterology] consults.” Sunanda Kane, MD, a gastroenterologist and professor of medicine at Mayo Clinic, in Rochester, Minn., said the new study provides a “good teachable moment. Many clinicians assume that a patient hospitalized with IBD needs to be NPO or on restricted caloric intake.” However, she pointed out an important limitation to the study: Patients with ulcerative colitis and Crohn’s disease were lumped together. “A patient with an obstruction certainly should not be fed but a patient with an abscess or just active ulcerative colitis can be,” Dr. Kane said. Maria Abreu, MD, a gastroenterologist at the University of Miami’s Miller School of Medicine, in Florida, said the findings point to the need to use electronic health records “to encourage doctors to reassess a patient’s ability to eat solid food or at least nutritional drinks. “Most of us doctors don’t realize how awful it is to not eat,” she said. —Lynne Peeples

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

Home continued from page 1

behavioral health, said Eva Szigethy, MD, PhD, the team’s co-director. Dr. Szigethy said this is because psychosocial and behavioral elements of health have a profound effect on IBD outcomes. “Sixty to 70% of IBD patients who utilize the largest portion of resources have severe pain, depression, anxiety and fatigue, all of which can worsen inflammation,” said Dr. Szigethy, associate professor of psychiatry, pediatrics and

medicine; director of the Visceral Inflammation and Pain Center in the Division of Gastroenterology; and director of the Medical Coping Clinic at Children’s Hospital of Pittsburgh. To manage these comorbidities, the UPMC IBD medical home includes a team of social workers, psychologists and psychiatrists, along with gastroenterologists, nurses and a nurse practitioner. The nurses and nurse practitioner serve as “air traffic controllers,” Dr. Szigethy said, directing patients to the appropriate provider, while social workers help

Table. Impact of Behavioral Intervention on Annual Health Care Use Preintervention

Postintervention

Annual mean (SD)

P value

Primary care physician Visits (n=14)

2.9 (1.5)

1.6 (1.5)

0.015

IBD Center Visits (n=53)

3.5 (2.7)

2.8 (3.4)

0.013

Emergency Department Visits (n=23)

3.6 (3.4)

2.3 (2.6)

0.034

Hospital Days (n=17)

10.4 (8.3)

6.2 (11.7)

0.061

IBD, inflammatory bowel disease; SD, standard deviation

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patients tap into their social supports and remove barriers to medication access and adherence. For their part, psychiatrists and psychologists provide medical and behavioral mental health interventions, Dr. Szigethy explained. She and her colleagues have yet to collect outcomes and cost data for the medical home, but Dr. Szigethy said the same behavioral health model was rolled out previously as part of UPMC’s IBD center, with positive effects. “We found reductions in primary care visits, gastroenterologist visits, emergency department use and fewer days spent in hospital,” Dr. Szigethy said (Table). As for the gastroenterologists who are part of the UPMC IBD medical home, they now follow published clinical care pathways and are more conservative in their use of expensive interventions such as surgery, said Miguel Regueiro, MD, codirector of the program and clinical head and co-director of the IBD center in the Division of Gastroenterology, Hepatology and Nutrition at UPMC.

GASTROENTEROLOGY & ENDOSC OPY NEWS • MAY 2015

“In the past, we’d orderr tests, use medicatioons and send patients for endoscopiees and surgeries without considering ccost,” Dr. Regueiroo said. “Now, we foollow evidencebased pathways and questiion whether a medication or test or su urgery is necessary. T This has led to improved care and also decreased cost.”” Medical home pattients residing a distance from UPMC also have the option of telemedicine services, including access to the behavioral health care and some medical interventions, like adjustments to medication regimens, Dr. Regueiro said. Offering this service reduces interruptions to patients’ daily activities and consequent effects on quality of life. According to Dr. Regueiro, UPMC’s IBD medical home is currently funded by only one insurer, which means the team has limited initial enrollment to a subgroup of 15% of their IBD patients who they have found account for half of all spending on IBD treatment. “If results with this segment of our IBD population are favorable, I think other payors will pay for medical home care for their insured patients,” Dr. Regueiro said.

Project Sonar. Patients can access the site through a computer or mobile device and complete a symptom severity questionnaire. If the severity of their illness worsens, clinicians can intervene early in the hope of preventing hospitalizations. “Part of the reason our model is techheavy is that many of our Crohn’s patients are younger and technologically well connected. We have to bend to how they prefer to communicate, and they’d rather do that online than over the phone,” Dr. Kosinski said. His team is focusing the medical home initiative on patients with Crohn’s

disease initially for the sake of simplicity in evaluating the models’ impact, and they will include patients with ulcerative colitis if the program is successful. Along with Project Sonar and nurse care coordination, the third component of the medical home paradigm is mandatory adherence to the American Gastroenterological Association’s Crohn’s disease clinical care pathways, Dr. Kosinski said (gastro.org/practice/clinical-service-line/ ibd-clinical-service-line). “However, I think the biggest drivers of reduced hospitalizations have

been better communication through the patient portal and directly with our nurses,” said Dr. Kosinski, who noted that the model has cut Crohn’s disease– related hospitalizations by 50%. As to whether the tech-heavy Chicago model is superior to the multidisciplinary, behavioral health–focused UPMC program, or vice versa, Dr. Allen said the data are not yet available. “There are many different ways a medical home can be constructed,” he said. “Now, we need to wait and see which model is most effective.” —David Wild

Ingenuity Delivered!

Illinois Medical Home Focuses on Patient–Provider Communication UPMC’s IBD medical home model bears some similarity to the one developed by Lawrence Kosinski, MD, MBA, and his colleagues at Illinois Gastroenterology Group, a Chicago-based medical practice including 45 gastroenterologists. Like the multidisciplinary team included in UPMC’s medical home, the medical home that Dr. Kosinski and his colleagues built includes gastroenterologists and IBD nurse care managers, who bring in other specialists when needed. Dr. Kosinski and his colleagues developed their medical home approach after conducting a claims database analysis in collaboration with Blue Cross Blue Shield Illinois. “The data showed us that a significant portion of spending among Crohn’s disease patients was for the treatment and hospitalization of patients with complications, and that less than half of hospitalized Crohn’s disease patients had met with a provider within the 30 days prior to admission,” Dr. Kosinski said. To preempt those urgent cases, he and his colleagues now communicate with their patients at least once per month through a Web portal called

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

Biliary Tract Cancers a ce s S Show o Tumor-Specifi u o Spec c Gene Ge Features SAN FRANCISCO—Two-thirds of biliary tract cancer patients harbored genomic alterations that could soon guide the selection of approved targeted therapies or access to novel therapies available in clinical trials, according to findings presented at the 2015 Gastrointestinal Cancers Symposium. “Given the limited treatment options and poor prognosis of patients with biliary tract cancers, and the diversity of clinically relevant alterations that have been identified in this study … comprehensive genomic profiling [has] significant potential to maximize the identification of new treatment paradigms and meet an unmet clinical need for this devastating disease,” said investigator Jeffrey Ross, MD, medical director of Foundation Medicine and chair of the Department of Pathology and Laboratory Medicine at Albany Medical College, in New York. According to Dr. Ross, biliary tract cancers—including intrahepatic cholangiocarcinoma (IHCCA), extrahepatic cholangiocarcinoma (EHCCA) and gallbladder carcinomas (GBCA)—typically present at an advanced stage and are refractory to conventional cytotoxic chemotherapy. The study’s goal was to determine whether comprehensive genomic profiling of IHCCA, EHCCA and GBCA would reveal distinctive patterns of genomic alterations and identify clinically relevant alterations that could lead to targeted therapies. The study used a hybrid capturebased next-generation sequencing assay that evaluated the coding exons of 315 cancer-related genes and 47 introns in genes commonly rearranged in cancer. DNA was extracted from 554 biliary tract carcinomas, including 412 cases of IHCCA, 57 cases of EHCCA and 85 cases of GBCA. The overall number of genomic alterations per patient was similar among the various types of biliary tract carcinomas (Table). The clinically relevant alterations—the so-called “actionable alterations” per patient—also were the same: two for all three tumor types. For patients with IHCCA, “There was a wide diversity in the type of alterations,” Dr. Ross said. TP53 was the most commonly altered gene, followed by P16, KRAS S and others. For the GBCA group, TP53 also was the most commonly altered gene. KRAS S was the most commonly altered gene for EHCCA, followed by TP53 and P16. IHCCA, EHCCA and GBCA all were noted to have frequent genomic alterations associated with cell cycle regulation (CDKN2B) and chromatin remodeling ((ARID1A). IHCCA was

These ‘results validate some others that have looked at the biliary tract, so it’s very exciting—there’s huge promise here. However, we still need to do this in a clinical trial, because a mutation does not necessarily mean it will benefit with an agent

of patients with GBCA. The ERBB2 amplification rate was lower in patients with EHCCA (11%) and even lower in patients with IHCCA (4%). Dr. Ross highlighted several cases in which patients responded to targeted therapies in each of the three tumor types. For example, one patient with an EGFR-amplification GBCA responded to neoadjuvant erlotinib (Tarceva, Genentech) therapy when it was combined with systemic chemotherapy. In another case, a GBCA patient with FGFR3 fusion demonstrated disease stability after four months of the investigational agent dovitinib. “This suggests, that targeting the FGFR fusion has clinical efficacy for this tumor type,” Dr. Ross said. Dr. Ross stressed that the findings were preliminary and were meant to identify potential therapeutic targets. “We did not use this study as a prognostic test; it was only done to search for therapy targets,” he said. “We do not have the kind of outcomes data for the entire cohort to be able to put prognostic results into the study at this point, but we’re hoping to get that kind of follow-up.”

Clinical Trials Needed

that hits the mutation.’ —Laura A. Dawson, MD

Table. Genomic Alterations in Biliary Tract Cancers Genomic Profiling Findings

EHCCA

GBCA

IHCCA

Overall genomic alterations per patient

4.4

3.6

Clinically relevant genomic alterations per patient

2.1

ERBB2 amplification, %

BRAF F substitutions, %

KRAS substitutions, %

PI3KCA substitutions, %

FGFR1-3 fusions and amplifications, %

CDKN2A/B loss, %

IDH1/2 substitutions, %

ARID1A alterations, %

MET T amplification, %

EHCCA, extrahepatic cholangiocarcinoma; GBCA, gallbladder carcinoma; IHCCA, intrahepatic cholangiocarcinoma

further characterized by FGFR fusions, IDH1/2 substitutions, BRAF F substitutions and MET amplification, with a low KRAS mutation frequency. IHCCA and GBCA had frequent ERBB2 amplifications and PI3KCA/MTOR pathway

alterations. KRAS mutation frequency was high in EHCCA and low in GBCA. Dr. Ross noted that amplification of the ERBB2 gene—potentially the same as in breast and upper gastroesophageal carcinomas—was found in 16%

Laura A. Dawson, MD, a researcher for the Cancer Clinical Research Unit at the Princess Margaret Cancer Centre, in Toronto, Canada, said, “I think moving forward, we need to change the way we make treatment decisions, and I think this is the way of the future—to look at not only pathological or anatomical histology but profiling as well. [These] results validate some others that have looked at the biliary tract, so it’s very exciting—there’s huge promise here. However, we still need to do this in a clinical trial, because a mutation does not necessarily mean it will benefit with an agent that hits the mutation. So, I strongly believe we need to incorporate profiling into trials.” Although Dr. Dawson said she would use profiling with her patients, she cautioned that it would be unethical to do so without the proper mechanism to treat the patient, such as a clinical trial. “And for trials that aren’t using profiling,” she concluded, “I strongly recommend the archiving of tissue—or to look for serum and circulating DNA— so we can learn in a prospective setting whether targeting actual mutations should differ from standard care.” —Chase Doyle Dr. Ross is the medical director of Foundation Medicine, whose assay was used in the study. Dr. Dawson reported no relevant financial conflicts of interest.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

Gastrointestinal Cancers:

Are We Ready for Molecular Profiling? SAN FRANCISCO—In a debate at the 2015 Gastrointestinal Cancers Symposium, Peter J. O’Dwyer, MD, the program leader in developmental therapeutics at the University of Pennsylvania’s Abramson Cancer Center, in Philadelphia, advocated the merits of ordering molecular profiling for patients, whereas Neal J. Meropol, MD, associate director of clinical programs at University Hospital’s Seidman Cancer Center, in Cleveland, argued that such testing is unnecessary and costly.

patients could have a therapy that was directed by the assay.” According to Dr. O’Dwyer, the distribution found at the University of Pennsylvania was similar to databases with much larger numbers of colorectal cancer, and there also is applicability outside colon cancer, across other malignancies.

Whom To Test? Acknowledging that clinicians can’t at this point recommend “who should get tested,” Dr. O’Dwyer said, “Genetic

‘Sensitivity for base substitution is in excess of 99.9% positive predictive value for these assays, which is very high ....’ —Peter J. O’Dwyer, MD

Highlighting the decreasing costs and increasing availability of molecular profiling, Dr. O’Dwyer said that nextgeneration sequencing panels have been made available at many academic and commercial institutions due to a dramatic reduction in sequencing costs. “We’re currently around the area of $5,000 to $6,000 per test for comprehensive genomic sequencing,” he said. “We’re well within the range of feasibility already, and we expect them to become less expensive.” He emphasized the flexible nature of the technology, which allows for broad coverage of the whole expressed panel or highly targeted areas of sequence. “Is it valid?” he rhetorically asked the audience. “Sensitivity for base substitution is in excess of 99.9% positive predictive value for these assays, which is very high indeed. … So, yes, I think the technoology is robust and reliable.”

may not work, and they have side effects. This should not be our routine approach with patients.” For Dr. Meropol, the limited availability of investigational drugs and clinical trial sites provided further evidence of the drawbacks to genetic profiling. “Not everybody lives in close proximity to a research center,” he said, “and getting compassionate access to a new drug in development is a logistically complicated process.”

Limitations and Risks

Costly Interventions, Unintended Consequences

In opposition to Dr. O’Dwyer’s position, Dr. Meropol outlined reasons why clinicians should hesitate before succumbing to pressure to routinely test all tumors. One item on his list of concerns was assay platform limitations. He noted potential variability in the sensitivity and specificity of numerous platforms being promoted. “How are

Payment also is a problem, Dr. Meropol argued. Increasingly, payors are scrutinizing off-label use of expensive targeted agents, resulting in costs falling on patients. “Recommending cancer drugs with high copays may not be ethical without strong evidence that they are going to help that individual

‘These are costly interventions. They may not work and they have side effects. This should not be our routine approach with patients.’ —Neal J. Meropol, MD

Finding Actionable Mutations Dr. O’Dwyer described his cen-ter’s experience with personalized d diagnostics for colorectal canceer to support the idea that such testing provides information that can n be clinically useful. Of the 101 pattients sequenced using Illumina MiSeq platform, 95% had at least one mutaation, with a median of two and a meaan of 2.46 mutations. “We conservatively used about seven abnormalities that we defined as actionable, either through standard therapies or clinical trials,” he said, “and we determined 42% of

those too sick to avail [themselves] of a treatment are not good candidates because testing can’t do them any good,” he said. “I think it’s also important to recognize that positive findings are not equally likely across all [gastrointestinal] malignancies.” He concluded that given that response to therapy based on genomic profiling currently is anecdotal, the key benefit to a patient is the potential eligibility for a research trial.

analysis is not really standard of care and hasn’t been validated yet to contribute to the overall benefit of patients.” However, he did recommend who shouldn’t get tested. “Patients who don’t need treatment or

the genes selected for these panels?” he asked. “Does the platform look at the transcriptome or just the genome? Are we looking at epigenomic changes? What’s the turnaround time for results? Who is interpreting? Who is annotating? And what is the cost?” Dr. Meropol also cited the complexity and heterogeneity of tumors as a concern. Depending on where one biopsies the tumor, the mutations identified may differ am among sites. “Not all of these tumors are th he same,” he said. “Although they may loook the same under a microscope, colon cancers and gastric canccers are extremely complex an nd extremely heterogenous iin terms of their molecular profile.” According to Dr. Meropol, definitions used for identifying drivers in a cclinical trial are not yet good en nough for routine clinical care. Nor does finding a single driver mutation guarantee a single, effective drug intervention because of “crosstalk” between pathways that occurs downstream of a key mutation. “These are costly interventions,” he said. “They

patient,” he said. Given the potential for confusion over interpretation, Dr. Meropol stressed the importance of knowing who is interpreting the data and making recommendations. He concluded his talk with a focus on the patients. “We don’t want to give our patients false hope,” he said. “We don’t want to subject them to the risks of needless biopsies, and we don’t want to subject them to the financial burden of therapies and procedures that are not destined to help.” After both speakers completed their presentations, the audience response shifted somewhat. After the presentations, fewer participants stated that they would routinely order genomic tests than had indicated they would in a baseline survey before the debate. Nevertheless, 60% of the audience polled still said they would recommend an assay for a patient with metastatic colon cancer refractory to treatment if the gene-sequencing panel was covered by insurance. —Chase Doyle Dr. Meropol reported that he has consulted for BioMotiv. Dr. O’Dwyer reported no relevant financial conflicts of interest.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

Study: Nearly 500,000 Americans Suffered From C. difficile Infections in a Single Year

ne would be hard-pressed to find a U.S. health care worker who was unaware of the devastation that Clostridium difficilee can cause in the hospital setting, but it is also causing considerable damage in the community, according to Michael Bell, MD, who spoke during a telebriefing sponsored by the Centers for Disease Control and Prevention (CDC). In 2011, C. difficile caused approximately 453,000 infections; 29,000 of those patients died within 30 days of the initial diagnosis of C. difficile (N Engl J Medd 2015;372:825-834). Approximately two-thirds of the C. difficile infections (CDIs) were found to be associated with an inpatient stay in a health care facility, but only 24% of the cases occurred while patients were hospitalized. Almost as many cases occurred in nursing homes as in hospitals, and the remainder of the health care–associated (HCA) cases occurred among patients who were recently discharged from a health care facility. More than 80% of the deaths associated with C. difficile occurred among Americans aged 65 years or older. “Infections have become increasingly common over the last few decades and are seen in patients in health care facilities, as well as people in the communities,” Dr. Bell explained. “In the past, patients infected with C. difficilee have had diarrhea that was often perceived as a nuisance but was not a major problem. “Unfortunately, the type of C. diff circulating in the U.S. today produces a powerful toxin that can cause a truly deadly diarrhea,” said Dr. Bell, who is deputy director of the Division of Healthcare Quality Promotion in the CDC’s National Center for Emerging and Zoonotic Infectious Diseases, in Atlanta. Previous studies have indicated that C. difficilee has become the most common microbial cause of HCA infections in

U.S. hospitals and costs up to $4.8 billion each year in excess health care costs for acute care facilities alone. The new study found that one of every five patients with an HCA CDI experienced a recurrence of the infection, and one of every nine patients aged 65 or older with an HCA CDI died within 30 days of diagnosis.

the CDC said. When an individual takes broad-spectrum antibiotics, beneficial bacteria that are normally present in the gut and protect against infection can be suppressed for several weeks to months. During this time, patients can develop C. difficilee picked up from contaminated surfaces or spread person to person. Unnec-

‘Unfortunately, the type of C. diff circulating in the U.S. today produces a powerful toxin that can cause a truly deadly diarrhea.’ —Michael Bell, MD “C. difficilee infections cause immense suffering and death for thousands of Americans each year,” said CDC Director Tom Frieden, MD, MPH. “These infections can be prevented by improving antibiotic prescribing and by improving infection control in the health care system. The CDC hopes to ramp up prevention of this infection by supporting state antibiotic resistance prevention programs in all 50 states.”

Patients at Highest Risk Patients who take antibiotics are most at risk for developing CDIs. More than half of all hospitalized patients will get an antibiotic at some point during their hospital stay, but studies have shown that 30% to 50% of antibiotics prescribed in hospitals are unnecessary or incorrect,

Aspirin continued from page 11

association was found between regular use and risk for CRC. Among participants with two rare genotypes of rs2965667 (TA or AA, 4% of participants; P=0.002), P aspirin and/or NSAID use was associated with a higher risk for CRC. In this genome-wide investigation of gene-by-environment interactions, “use of aspirin, NSAIDs, or both was associated with lower risk of colorectal cancer, and the association of these medications with colorectal

essary antibiotic use and poor infection control may increase the spread of C. difficilee within a facility and from facility to facility when infected patients transfer, such as from a hospital to a nursing home. Older Americans are especially vulnerable to this deadly diarrheal infection. The CDC study found that one of every three CDIs occurs in patients 65 years or older and two of every three HCA CDIs occur in patients 65 years or older. More than 100,000 CDIs develop among residents of U.S. nursing homes each year. Women and whites are at increased risk for CDI.

Improving Antibiotic Use Critical For Prevention Although more than 150,000 of the 500,000 infections in the new study

cancer risk differed according to genetic variation at two SNPs at chromosomes 12 and 15. Validation of these findings in additional populations may facilitate targeted colorectal cancer prevention strategies,” the researchers wrote. Considerable evidence demonstrates that use of aspirin and other NSAIDs is associated with a lower risk for CRC, the researchers said in their paper. However, the mechanisms behind this association are not well understood. Routine use of aspirin, NSAIDs or both for prevention of cancer is not recommended because of uncertainty about the risk–benefit profile.

were community-associated and had no documented inpatient health care exposure, a separate recent CDC study found that 82% of patients with communityassociated CDIs reported exposure to outpatient health care settings such as doctors’ or dentists’ offices in the 12 weeks before their diagnosis; this finding underscores the need for improved antibiotic use and infection control in these settings as well. It is estimated that more than 50% of antibiotics are prescribed unnecessarily in outpatient settings for upper respiratory infections like cough and cold illness, most of which are caused by viruses. Another recent CDC study showed that a 30% decrease in the use of antibiotics linked to CDIs in hospitals could reduce the infections by more than 25% in hospitalized and recently discharged patients. A new retrospective study from a Canadian hospital found that a 10% decrease in overall antibiotic use across different wards was associated with a 34% decrease in CDIs. A third CDC study among patients without a recent hospitalization or nursing home stay (i.e., community-associated cases) found that a 10% reduction in the use of all antibiotics in outpatient settings could reduce CDIs by 16%. In England in recent years, the number of CDIs has been reduced by well over 60%, largely due to improvements in antibiotic prescribing. To help hospitals develop antibiotic stewardship programs, the CDC has developed several tools, including a list of core elements of hospital antibiotic stewardship programs. The CDC is also working with states to improve outpatient prescribing and to implement stewardship across the continuum of care and has provided a variety of resources through the “Get Smart: Know When Antibiotics Work” and “Get Smart for Healthcare” campaigns. —Marie Rosenthal

Understanding the relationship between genetic markers and use of drugs, such as aspirin and NSAIDs, might help identify the subgroups that could benefit most from this prophylaxis. “In the not-too-distant future, it will be possible to affordably and efficiently conduct genetic testing in healthy individuals to more accurately define benefits and risks of interventions intended to decrease risk of disease,” wrote Richard C. Wender, MD, of the American Cancer Society, in Atlanta, in an accompanying editorial ((JAMA A 2015;313:1111-1112). —GEN Staff

THEY TALK BLOATING, GAS, RUMBLING, DISCOMFORT

WE TALK SCIENCE ACTIVIA® is a probiotic yogurt that may help reduce the frequency of minor digestive issues like bloating, gas, rumbling, and discomfort when consumed twice per day for four weeks as part of a balanced diet and healthy lifestyle. Figure 1 Forest Plot of Composite Score of the Frequency of Minor Digestive Issues LSmeans = least squares means; CI = confidence interval; N = number of subjects that completed study LSmeans and 95% CI

LSmeans

95% CI

Study 1

199

– 0.64

[–1.19; –0.08]

Study 2

336

– 0.41

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Two double-blind, randomized, placebo-controlled studies, and a pooled analysis of these studies, show that ACTIVIA® may help reduce the frequency of minor digestive issues like bloating, gas, rumbling, and discomfort.1,2 Both studies were designed to investigate the effect of ACTIVIA® on different gastrointestinal (GI) outcomes, including GI well-being and frequency of minor digestive issues, in healthy women lacking any diagnosed GI disorders. Criteria used for recruitment included the presence and frequency of minor digestive issues. Subjects were randomized to consume ACTIVIA® or a control dairy product twice a day for 4 weeks. The frequency of individual digestive issues was evaluated weekly throughout the study and a composite score was calculated ranging from 0 to 16. Results were reported in the form of least squares means (LSmeans). In both studies, the composite score of minor digestive issues over the fourweek test period in the ACTIVIA® group was significantly lower (P<0.05) than that in the control group [Study 1: LSmean –0.64; 95% CI (–1.19; –0.08), Study 2: LSmean –0.41; 95% CI (–0.79; –0.02)] (Figure 1). Results from the pooled analysis confirmed these findings [LSmean –0.48; 95% CI (–0.80; –0.16)]2 and strengthen the conclusion that ACTIVIA® may help reduce the frequency of minor digestive issues such as bloating, gas, rumbling, and discomfort when consumed twice per day for four weeks as part of a balanced diet and healthy lifestyle.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

Interventions continued from page 1

At the 2014 meeting of the American College of Gastroenterology, Yehuda Ringel, MD, professor of medicine and chief of the Division of Gastroenterology at Rabin Medical Center, in Petah Tikva, Israel, discussed targeted intestinal microbiota (IM) intervention for the treatment of three GI conditions: antibiotic-associated diarrhea (AAD), irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). “When we examine the role of intestinal microbiota in these conditions, we need to address a few big questions,” Dr. Ringel said. First, “does the IM in patients with a specific condition differ from the IM in healthy individuals?” In patients with IBS, differences do seem to exist. A study conducted by Dr. Ringel and his colleagues found different bacteria in fecal samples of patients with diarrhea-IBS (D-IBS) and healthy controls (Neurogastroenterol Motil 2012;24:521-530). They could even identify differences in specific bacteria. “For example, Faecalibacterium prausnitziii was much lower in D-IBS patients compared with controls,” he said. Researchers also have found differences in the microbial composition in people with Crohn’s disease (CD) compared with healthy controls. Differences were seen too between ileal and colonic CD phenotypes (Gastroenterology 2010;139:1844-1854). “Both [CD phenotypes] are different from ulcerative colitis patients,” who seem to differ less from healthy controls, Dr. Ringel said.

Proof in the Petri Dish? The second big question is if the IM differs between GI patients and healthy people, does it matter? In AAD, and in patients with Clostridium difficilee infection in particular, antibiotic treatment clearly alters the colonic microflora. “This leads to intestinal dysbiosis, which enables C. diff colonization and toxin production,” Dr. Ringel said. Depending on the patient’s immune system, this can result in diarrhea and colitis. The pathogenesis of IBS remains unknown, but it may involve interactions between the IM, the individual immune

system and the brain–gut axis ((Am J Physiol Gastrointest Perhaps the strongest evidence for the use of probiotLiver Physiol 2013;305:G529-G541). “All affect intestinal ics in GI disorders is in the prevention of pediatric AAD, physiology and symptoms,” Dr. Ringel said. Dr. Ringel said, pointing to a review suggesting probiIn IBD, too, altered IM may otics can reduce the incidence of drive the chronic inflammation ‘If I were a patient with AAD (Cochrane Database Syst Rev that ultimately damages the epi2013;5:CD006095). Their use is thelial barrier. “So I believe there significant IBS symptoms, not supported in the most recent is a growing body of evidence that I would stay on [the lowACG guidelines specifically for alteration in the IM resulting in prevention of recurrent C. diff FODMAP] diet as long as I felt dysbiosis is an important factor infection, but that lack of recomin the pathogenesis of these three it was tolerable, reintroducing mendation is a topic of debate. conditions,” Dr. Ringel said. “We had some differences of items one by one to see The third big question is what opinion among contributors to the impact interventions targeting the what effect they have on my ACG guidelines,” said Dr. Mellow, IM—diet, probiotics and antibiot- symptoms.’ who wrote the section on prevenics—may have on GI disorders. tion of C. diff. f “My own feeling is —Mark H. Mellow, MD “There has been a lot of interthat the bacterial probiotics curest in the role of diet in IBS,” Dr. rently on the market are so benign Ringel said—especially in the low-FODMAP diet, in there are almost no contraindications to their use, and a few which the elimination of highly fermentable short-chain studies show they benefit in that circumstance.” He noted carbohydrates has been shown to significantly improve the exception of Saccharomyces, which “is more aggressive symptoms such as flatulence, bloating and diarrhea. and should be avoided in patients with altered immunity.” Some recommend a low-FODMAP diet as a first-line In IBS, certain probiotics do appear to have a positive, therapy for IBS, but Dr. Ringel cautions it may have a if modest, effect. In IBD, some data show a benefit in significant and potentially detrimental effect on patients’ primary prevention of pouchitis after surgery or secondoverall nutrition and levels of beneficial bacteria (e.g., ary prevention following such an event, but little evidence Bifidobacterium) over time. “We’re not sure what happens supports the use of probiotics in other forms of IBD. [in the] long term,” he said. Antibiotics have been shown to relieve symptoms in In contrast, Dr. Mellow said he endorses the low- IBS patients somewhat, “but the effect may go beyond FODMAP diet without reservation. “It seems to be their direct impact on the IM, and we are not sure of the effective and harmless,” he said. “If I were a patient with long-term effects,” Dr. Ringel said. In IBD, “the overall significant IBS symptoms, I would stay on that diet as take-home message [from various studies] is that antibiotlong as I felt it was tolerable, reintroducing items one by ics may induce remission in active CD and ulcerative colione to see what effect they have on my symptoms.” tis, though the data are difficult to interpret because there In IBD, however, no clinical evidence at this point were many antibiotics used in different combinations.” favors one diet over another. “A meta-analysis [Cochrane Interventions targeting the intestinal microbiome Database Syst Rev v 2007;24:CD000542] comparing dif- through diet, probiotics and antibiotics have the potenferent diets on the induction of remission in active CD tial to alter the composition and function of the IM found no significant difference between the diets,” Dr. and may induce beneficial clinical effects. “But there Ringel said. “They concluded that conventional therapies are limitations to our knowledge,” Dr. Ringel said. “We including corticosteroids are more effective than any of certainly need more high-quality research.” the dietary interventions.” —Monica J. Smith

Nothing To Sneeze at: Allergy Med Blocks HCV in Mice

n over-the-counter drug indicated to treat allergy symptoms limited hepatitis C virus (HCV) activity in infected mice, according to a National Institutes of Health study. The results suggest that the drug, chlorcyclizine HCl (CCZ), potentially could be used to treat the virus in people (Sci Transl Medd 2015;282:282ra49). HCV causes liver inflammation and often leads to serious complications such as cirrhosis. Early diagnosis and treatment of HCV can prevent liver damage, but the medications to treat HCV can reach tens of thousands of dollars. “Although hepatitis C is curable, there is an unmet need for effective and affordable medication,” said lead researcher T. Jake Liang, MD, senior investigator at

the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health (NIH). “CCZ is a promising candidate for part of a treatment regimen for this potentially life-threatening disease.” The study found that CCZ blocked the early stage of HCV infection likely by impairing the ability of the virus to enter human liver cells grafted in the mice. The outcome was similar to that of commonly used antiviral drugs but without the toxic side effects of those drugs. “Using an innovative high-throughput screening process, we identified CCZ as a potent inhibitor of hepatitis C,” said Anton Simeonov, PhD, acting scientific director of the NIH’s National Center for Advancing Translational Sciences

(NCATS), which collaborated in the study. “Identifying already approved drugs from the NCATS Pharmaceutical Collection may offer a faster route to potential discovery of treatments for all diseases.” The researchers will next study the drug’s effects on individuals. CCZ is indicated for the treatment of allergies, not for HCV. “People should not take CCZ to treat their hepatitis C until it has been demonstrated that CCZ can be used safely and effectively for that purpose,” Dr. Liang cautioned. HCV infection affects an estimated 150 million individuals worldwide. Patients with HCV interested in participating

in clinical research on CCZ may call (866) 444-2214 (TTY [866] 411-1010), or see ClinicalTrials.gov identifier: NCT02118012 for information. Support for both studies comes from the intramural research programs of the NIDDK and NCATS and from Hiroshima University. —Marie Rosenthal

H E M OS TA S I S

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

Celiac Disease May Cause Female Infertility

linicians should consider celiac disease as a possible cause of infertility in women, particularly when other causes have been ruled out, according to a new study. Results from a meta-analysis of more than 400 women showed that those with unexplained infertility were six times more likely to have celiac disease than women in the general population. “If you look at all women being evaluated for infertility, celiac disease is not a very common cause, but if you look only at women with unexplained infertility— those who have had anatomic and other routine issues excluded as causes—celiac disease makes up a small but significant proportion of these women,” said Daniel Leffler, MS, MD, director of research at the Celiac Center at Beth Israel Deaconess Medical Center, in Boston. “The fact that untreated celiac disease is also associated with other poor pregnancy outcomes, such as recurrent pregnancy loss, warrants consideration of the disease in women with infertility,” said Dr. Leffler, who was not involved in the new research. Lead investigator Prashant Singh, MD, a resident physician in the Department of Medicine at Massachusetts General Hospital, in Boston, said there have been conflicting findings regarding a possible link between infertility and celiac disease (World J Gastroenterol 2010;16:5810-5814). Previous research also often has lacked adequate statistical power because of small study populations, Dr. Singh added. To capture a broad picture of the association between infertility and celiac disease, Dr. Singh and his colleagues

analyzed pooled data from five studies that documented rates of celiac disease in both women with infertility that was attributable to non-celiac causes and infertility that could not be explained by a common cause (box). They also included a control group of approximately 6,000 women from the general population.

[OR], 4.6; 95% confidence interval [CI], 2.2-9.7; P<0.01). Furthermore, when the researchers looked only at women with infertility that was not attributable to a known cause despite conventional workup, they again found that 3% (14 of 422) had celiac disease, translating to a sixfold

action explain how celiac disease can lead to infertility in some women. “The disease causes deficiencies in micronutrients, including selenium and folate, which are closely linked to fertility,” he said. “There have also been in vitro studies showing anti-tissue transglutaminase antibodies [which are present in celiac disease patients] can harm the placenta by adhering to trophoblastic cells of placenta and endometrial endothelial cells.” Although some evidence indicates that infertility can be reversed in women with

Studies of Celiac Disease Rates in Women With Infertility

According to Dr. Singh, all of the women were of reproductive age and had not been able to conceive despite multiple attempts over at least one year and without contraception. All cases of celiac disease in the studies were confirmed by serology testing and duodenal biopsies demonstrating villous atrophy. The researchers found that roughly 3% of women (12 of 449) with both explained and unexplained infertility had celiac disease, translating to a 3.5-fold increased risk for the condition compared with the pooled control group (odds ratio

Shamaly H, et al. Infertility and celiac disease: do we need more than one serological marker? Acta Obstet Gynecol Scand. 2004;83:1184-1188.

Tiboni GM, et al. Serological testing for celiac disease in women undergoing assisted reproduction techniques. Hum Reprod. 2006;21:376-379.

Meloni GF, et al. The prevalence of coeliac disease in infertility. Hum Reprod. 1999;14:2759-2761.

Collin P, et al. Infertility and coeliac disease. Gut. 1996;39:382-384.

Fasano A, et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med. 2003;163:286-292.

increase in risk compared with the control group (OR, 6; 95% CI, 2.4-14.6; P<0.05). Dr. Singh, who presented the study at the 2014 annual meeting of the American College of Gastroenterology (poster 187), said at least two mechanisms of

celiac disease who follow a gluten-free diet (Gut 2011;60:1023-1024), Dr. Singh said stronger data are needed to confirm this effect. —David Wild Drs. Leffler and Singh reported no relevant financial conflicts of interest.

At A Glance form in March. A copy of the document is available at https://www.aamc.org/ data/workforce/reports/. Figures reprinted with permission from the Association of American Medical Colleges.

f you think your call schedule is tough now, wait a decade. The Association of American Medical Colleges predicts a shortfall of between 46,100 and 90,400 physicians by 2025. The data come from a report titled “Complexities of Physician Supply and Demand: Projections from 2013 to 2025,” which was released in final

Active Physicians

14,000

Male

10,000 8,000 6,000

Female

4,000 2,000

950,000 911,400 906,700 893,100 890,300 885,900 865,000

900,000

850,000

— Demand (+ACA+MC) C C — Demand (+ACA) — Demand (+ACA + Retail Clinics) — Demand (Demographics — Demand (+ACA + APRN Moderate) — Demand (+ACA + APRN High)

800,000 778,200 750,000

ACA, Affordable Care Act; APRN,, advanced ad a ced ppractice act ce nurse u se

700,000 <30

Physician Age

2013

2017

2021

Year

2025

Projected Shortfall of Physicians

16,000

12,000

P j t dT Projected Total t l Ph Physician i i Shortfall, Sh tf ll 2013-2025 2013 2025

Projected Demand for Physicians, 2013-2025 Full Time Equivalent Physicians

Age Distribution of Active Physicians, 2013

120,000 110,500 100,000 90,400 80,000

ile

60,000

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2015 Rangee 46,100

40,000

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25th percen 20,000

3,200 2013

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

Pediatric Celiac Disease Diagnosis And Management Practices Concern Experts

national survey of pediatric gastroenterologists has revealed significant variation in the diagnosis and management of young patients with celiac disease. More than one-third (34.7%) of clinicians, for example, said serology findings alone would be enough to make a diagnosis of the condition—a stance not

supported by current guidelines from a major U.S. specialty group. Lead investigator Anthony Porto, MD, MPH, assistant professor of pediatrics and associate clinical chief in the Section of Pediatric Gastroenterology at Yale University, in New Haven, Conn., noted the North American Society for Pediatric Gastroenterology, Hepatology

and Nutrition (NASPGHAN) recommends that diagnoses be made using a combination of serology results and duodenal biopsies ((J Pediatr Gastroenterol Nutr 2005;40:1-19). Dr. Porto said he was particularly troubled that most physicians who said positive serology would suffice for a diagnosis also indicated that a level of tissue

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transglutaminase (tTG) immunoglobulin (Ig)A of at least 10 times the upper limit of normal would be enough for them to make a diagnosis. “Even ESPGHAN [European Society for Pediatric Gastroenterology, Hepatology and Nutrition] guidelines, which leave the option open to a diagnosis based on serology alone, indicate that an elevated tTG-IgA of at least 10 times the upper limit of normal alone is insufficient for a diagnosis, and that a positive endomysial antibody test and the presence of genetic markers are needed as well,” Dr. Porto said. Dr. Porto’s group posted its 18-item survey on a national pediatric gastroenterology online bulletin board. Of the 239 pediatric gastroenterologists who responded, 148 were academic practitioners, 62 were hospital-based clinicians and 29 were in independent practice or private clinics. Ninety-two respondents reported having been in practice for more than a decade (Table). Stefano Guandalini, MD, a co-author of the 2005 NASPGHAN guidelines and not involved in the study, echoed Dr. Porto’s concern with the finding that a substantial portion of surveyed physicians would diagnose celiac disease on tTG-IgA serology alone. “Basing a diagnosis solely on tTG titers that are often not even high is highly

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

Table. Survey Findings on the Diagnosis s and Management Of Pediatric Celiac Disease During endoscopic examination, 75% of respondents said they would obtain ≥5 duodenal biopsies, but 24.2% collect. When screening children <2 y, 90.6% of respondents said they use tTG-IgA level, which has a higher false-negative rate in this age group ((J Pediatr Gastroenterol Nutr 2008;47:428-435). Only 48.3% use deamidated anti-gliadin IgA. For IgA-deficient children, 12% said they would proceed directly to endoscopy without any further laboratory investigations, whereas 28.2% said they would test for HLA DQ-2/8, which are genetic markers of celiac disease. There was no consensus on how frequently to monitor a child once diagnosed with celiac disease.

dubious and blatantly wrong,” said Dr. Guandalini, professor and chief of pediatric gastroenterology at the University of Chicago, and founder and medical director of the University of Chicago Celiac Disease Center. He pointed to a finding from the survey indicating that some physicians would proceed with a diagnosis based only on tTG-IgA levels lower than 10 times the upper limit of normal. Dr. Guandalini also cautioned that skipping a biopsy could leave comorbid conditions undetected. In a letter he and a colleague published in 2013, they reported that 12% of children with celiac disease who had been diagnosed using serology alone could have additional undetected diagnoses such as peptic esophagitis, Helicobacter pylorii and eosinophilic esophagitis ((J Pediatr Gastroenterol Nutr 2013;57:e24). “If a patient has not undergone upper endoscopy as part of their diagnosis, they should be carefully monitored to ensure their symptoms resolve completely, and to rule out other diagnoses,” Dr. Guandalini told Gastroenterology & Endoscopy News. Dr. Porto said the survey results should prompt NASPGHAN to revise its nearly decade-old guidelines on management of celiac disease in children, or to support the adoption of more recent European guidelines.

“Issuing updated guidelines or adopting ESPGHAN guidelines would likely reduce delays in diagnosis and also decrease the burden on those patients who are inaccurately diagnosed with celiac disease and are asked to adhere to a gluten-free diet,” Dr. Porto said. Dr. Guandalini said NASPGHAN has no plans to revise the full celiac disease management guidelines. However, he said, the topic will be included in an upcoming position statement on the diagnosis and treatment of gluten-related disorders in children.

Those recommendations will closely reflect the 2012 ESPGHAN guidelines, he noted ((J Pediatr Gastroenterol Nutr 2012;54:136-160). In the meantime, Dr. Guandalini said, “careful adherence to ESPGHAN guidelines seems appropriate.” Dr. Porto presented the survey findings at NASPGHAN’s 2014 annual meeting (abstract 15). —David Wild Drs. Porto and Guandalini reported no relevant financial conflicts of interest.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

CO2 Monitoring Gets Mixed Reviews in Colono oscopy Study PHILADELPHIA— —The American Society of Anesthesiologists recommends capnographic monitoring for all endoscopic procedures, but it may not be warranted in patients undergoing moderate sedation for routine colonoscopy. In a recent study, researchers found that routine capnographic monitoring did not decrease the incidence of hypoxemia in colonoscopy patients, although it may reduce the incidence of more severe hypoxemic events.

“In the [gastroenterology] literature, capnographic monitoring has been shown to lower rates of hypoxemia in advanced endoscopic procedures with moderate sedation, upper endoscopy and colonoscopy in pediatric patients with moderate sedation, and colonoscopy in adults with propofol sedation,” said Paresh P. Mehta, MD, a consultant with Gastroenterology Consultants of San Antonio, Texas. Dr. Mehta helped conduct the study while at the Cleveland Clinic, in Ohio.

“There was no evidence to date that capnographic monitoring improves safety in adults undergoing colonoscopy with moderate sedation. The goal of this study was to evaluate whether capnographic monitoring reduces the incidence of hypoxemia in [that patient population],” said Dr. Mehta, who presented the study at the 2014 annual meeting of the American College of Gastroenterology (abstract 6). The final analysis of the randomized

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controlled trial included 234 patients undergoing routine colonoscopy with moderate sedation, using an opioid/benzodiazepine combination, at the Cleveland Clinic between December 2013 and March 2014. Pulse oximetry, heart rate, electrocardiography and intermittent blood pressure were monitored in all patients. An independent observer monitored capnographic data and prompted intervention based on apnea, hypoventilation and hypercarbia in the open arm group. “Interventions were completed in a stepwise fashion: initiating with verbal or physical stimulation, then increasing supplemental oxygen and finally withholding further medications if needed,” Dr. Mehta said. The study’s primary outcome was hypoxemia, defined as an oxygen saturation less than 90% for a minimum of 10 seconds in a one-minute period. A secondary outcome was severe hypoxemia, defined as oxygen saturation less than 85% at any time during the procedure. Hypoxemia occurred in 52% of the open capnography group and 55% of the capnography-blinded group, suggesting that monitoring made little difference in preventing the condition. However, Dr. Mehta’s team observed a significant difference for severe hypoxemia, which occurred in 5% of the open arm and 18% in the blinded arm. “The study evidence suggests that additional capnographic monitoring may not be as beneficial with moderate sedation when evaluating hypoxemia as a primary outcome, as opposed to its known benefit with deeper sedative medications, such as propofol,” Dr. Mehta told Gastroenterology & Endoscopy News. “However,

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

‘The study evidence suggests that additional capnographic monitoring may not be as beneficial with moderate sedation when evaluating hypoxemia as a primary outcome, as opposed to its known benefit with deeper sedative medications, such as propofol.’ —Paresh P. Mehta, MD we did find that it was able to lower rates of hypoxemia in subjects who experienced severe hypoxemia, and we need to further investigate these findings.” John R. Saltzman, MD, director of endoscopy at Brigham and Women’s Hospital and associate professor of medicine at Harvard Medical School, both in Boston, called the study “important.” “To my knowledge, this is the first study to evaluate the value of capnographic monitoring in routine endoscopy. Superficially, it was a negative study—no difference in terms of hypoxemia in the two groups. But it was a positive study in terms of severe hypoxemia in the activemonitoring group,” Dr. Saltzman said. “You might presume they prompted the patients to breathe and thus were able to prevent the oxygen level from falling.” The recommendation to use capnography in endoscopic procedures was based on data showing its usefulness in such complex procedures as endoscopic retrograde cholangiopancreatography and endoscopic ultrasound, Dr. Saltzman said, “but there were no well-done studies for colonoscopy and upper endoscopy, which are the majority of the procedures we do.” He added that the downside of capnographic monitoring includes the burden of training staff to interpret the data appropriately “so that physicians and nurses are not over-responding to things,” and the cost of equipment, which for practices that already have a monitor that measures carbon dioxide comes to about $10 per case for the disposable nasal cannula. The clinical significance of the findings is unclear, as outcomes were similar

for both arms of the study, he noted. “And that’s what we’ve seen in the past, where we’ve used sedation for years without capnographic monitoring and done it very safely,” he said. Dr. Saltzman’s hospital requires use of routine capnographic monitoring based on the anesthesia society’s recommendations. He noted that most insurers do not cover the cost of the disposable equipment, and that cost is not billed to the patient.

1978

—

Dr. Saltzman said it would be useful to study capnography for upper endoscopy in similar patients, and to try to identify populations that will benefit from capnographic monitoring. “In the meantime, we will continue to do routine capnographic monitoring as recommended,” he said, “but it may turn out that this is a very conservative approach that adds cost without much benefit.” —Monica J. Smith

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

HIV Coinfection No Longer a Barrier To Effective Hepatitis C Treatment BOSTON—Having both HIV and hepatitis C was once thought to be a major hurdle to successful treatment for the liver virus. No longer. Two new studies, TURQUOISE-I and ERADICATE, show that treatment with new direct-acting antivirals is producing cure rates between 90% and 100% in patients coinfected with HIV and the

hepatitis C virus (HCV). Researchers presented results from the two trials at the 2014 Liver Meeting of the American Association for the Study of Liver Diseases. “The overall message from these two studies is that HIV patients can expect to respond to the new hepatitis C treatments almost exactly the same as patients

without HIV. The effectiveness of the new regimens is excellent,” Luis Balart, MD, told Gastroenterology and Endoscopy News. Dr. Balart, chief of gastroenterology and hepatology at Tulane University School of Medicine, in New Orleans, was not involved with either study. Concurrent infection with HCV and HIV increases the complexity of

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treatment. According to the Centers for Disease Control and Prevention, HIV coinfection more than triples the risk for progressive liver disease, liver failure and liver-related death from HCV. In the past, simultaneous treatment of both viruses has been complicated by large pill burdens, drug interactions and overlapping toxicities. Until now, hepatitis C treatments have only been roughly half or two-thirds as effective in patients with HIV as they have been in patients without HIV, Dr. Balart said.

ERADICATE

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Shyam Kottilil, MD, PhD, professor of medicine at the University of Maryland, in Baltimore, presented results from the ERADICATE trial testing a fixed-dose combination of the NS5A inhibitor ledipasvir and the nucleotide analog polymerase inhibitor sofosbuvir (Harvoni, Gilead; abstract 84). NS5A is a membrane-associated phosphoprotein involved in HCV virion production. The trial enrolled 50 patients coinfected with genotype 1 HCV and HIV who had not yet received treatment for hepatitis. Patients received fixed-dose ledipasvir-sofosbuvir once daily for 12 weeks. The study included 13 patients who had not received antiretroviral therapy and 37 patients who were treated for their HIV infection with the combination of emtricitabine-tenofovir (Truvada, Gilead) plus efavirenz, rilpivirine (Edurant, Janssen) or raltegrevir (Isentress, Merck). Approximately 84% of the study population was black, and 74% had genotype 1a HCV infection. After four weeks of treatment, all 50 patients had undetectable HCV RNA; 49 had a sustained virologic response at 12 weeks post-treatment. There were no serious adverse events (AEs) related to the study drugs or discontinuations resulting from such events. Mild AEs experienced by less than 25% of patients included pain, fatigue, diarrhea, nasal congestion, headache, nausea, myalgia and gingivitis. There was one case each of pneumonia, a

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

‘The overall message from these two studies is that HIV patients can expect to respond to the new hepatitis C treatments almost exactly the same as patients without HIV. The effectiveness of the new regimens is excellent.’ —Luis Balart, MD

lipase elevation, a neutrophil decrease and an asymptomatic and transient elevation in liver enzymes. Hepatitis treatment did not interfere with HIV treatment, although one patient had a transient increase in HIV viremia after missing HIV medications for four days, according to the researchers. This patient experienced HIV resuppression without a change in the regimen. “In the past, interferon was used to treat HCV infection,” Dr. Kottilil explained. “HIV-infected patients have a poor response to interferon. The exact reason is not known, but it is believed that exhaustion of endogenous type I interferon response is commonly observed in these patients, making them less responsive to exogenous interferon. Recently, we have started treating these patients without the use of interferon and the results have been promising.”

patients who were receiving atazanavirritonavir were instructed not to take their usual stand-alone dose of ritonavir during the trial. Sustained virologic response rates were 93.5% in patients who received 12 weeks of treatment and 90.6% in patients with 24 weeks of treatment. The researchers characterized the treatment as well tolerated, with no treatment-emergent serious AEs or AE-related discontinuations. Two patients had a confirmed virologic relapse with resistance-associated variants at all three viral targets that were not present

at baseline. HIV-1 RNA suppression was maintained in the majority of patients during treatment with the study drug. According to Dr. Wyles, the efficacy in the ERADICATE and TURQUOISEI trials are similar. He pointed out that there were relatively few patients in either trial, thus creating wide confidence intervals for the end points. “I don’t think the viral responses are any different,” he said. “The main difference [between the two trials] is in terms of which HIV regimens were studied: no ritonavir-boosted protease inhibitors for ERADICATE and no

efavirenz for TURQUOISE-I.” Dr. Balart said both regimens were good options for coinfected patients. “These studies are good news. Both of the regimens show excellent results comparable to non-HIV infected patients.” —Kate O’Rourke Dr. Kottilil reported no relevant financial conflicts of interest. Dr. Balart is on the scientific advisory board of AbbVie and has received research funding from the company. Dr. Wyles has received research grants, paid to his institution, from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Merck and Vertex Pharmaceuticals, Inc.

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GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ MAY 2015

BC/BE GASTROENTEROLOGIST PENN HIGHLANDS HEALTHCARE is seeking a BC/BE GASTROENTEROLOGIST to join our Penn Highlands DuBois Gastroenterology practice. This practice offers a full range of endoscopic services including endoscopy, colonoscopy, capsule endoscopy, ERCP and spyglass. â&#x20AC;˘ April 2015 â&#x20AC;&#x201C; NEW GI Lab opening â&#x20AC;˘ Sign on Bonus â&#x20AC;˘ Relocation expenses reimbursed up to $10,000 â&#x20AC;˘ CME reimbursement and time â&#x20AC;˘ Malpractice and tail coverage paid â&#x20AC;˘ Medical, Vision and Dental Insurance â&#x20AC;˘ 2 Retirement Plan Options â&#x20AC;&#x201C; dollar for dollar match up to 4% after 1 year of employment â&#x20AC;˘ 25 PTO days/year, 10 Sick days/year Penn Highlands is an integrated healthcare delivery system serving eight counties all within the beautiful, rolling hills of Central Pennsylvania. Just a short drive away from State College and Pittsburgh - whether you enjoy the theatre or the beauty of our four seasons, we offer you a rewarding, challenging career and a well-balanced lifestyle. Visit our website at www.phhealthcare.org. Please send CV to Wayne Saxton, Physician Recruiter at dwsaxton@phhealthcare.org or call at 814-375-3793.

Gastroenterologist Opportunity Geisinger Health System (GHS), a national leader in quality and integrated healthcare is seeking a BC/BE Gastroenterologist with an interest in ERCP, motility or IBD to join its innovative practice at Geisinger Medical Center in Danville, PA. Ability to perform ERCP will be supported in a new state-of-the-art endoscopy suite with 3 dedicated advanced procedure rooms. Become part of a closely integrated department comprised of more than 23 gastroenterologists, 3 hepatologists and 10 fellows with some of the best resources available for academic and clinical practice. Call is equally shared and is no more than 5 to 6 weeks per year. Transplant Hepatology, and our Gastroenterology and Advanced Endoscopy fellowship programs are located at Geisinger Medical Center. As a part of Geisingerâ&#x20AC;&#x2122;s team, you will work in an academic environment, backed by the resources of one of the nationâ&#x20AC;&#x2122;s most progressive integrated health systems. Enjoy the balance of a favorable call

schedule with the collegiality of a unique practice and surrounding community that offers a low cost of living, superb public schools, numerous outdoor and cultural activities, and easy access to major metropolitan areas including New York City, Baltimore, Philadelphia and Washington, D.C. Geisinger Health System serves nearly 3 million people in Northeastern and Central Pennsylvania and has been nationally recognized for innovative practices. A mature electronic health record connects a comprehensive network of 9 hospital campuses, 43 community practice sites and more than 1,200 Geisinger primary and specialty care physicians. Discover for yourself the Geisinger difference.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

PRESBYTERIAN Albuquerque, NM

As a gastroenterologist, you have options.

Presbyterian Healthcare Services is seeking Board Certiﬁed Gastroenterology trained physicians to join our established practice of 11 physicians, 2 Gastroenterology Hospitalists and 7 advanced practitioners. Our medical group employs more than 600 primary care and specialty providers and is the fastest growing employed physician group in New Mexico. Presbyterian Healthcare Services is a locally owned, not-for-proﬁt organization based in Albuquerque. Our integrated healthcare system includes eight hospitals in seven New Mexico cities, a medical group, multispecialty clinics and a health plan (over 400,000 members). We have been proudly providing care to New Mexicans for 105 years. In addition to a guaranteed base salary we also offer a sign on bonus, incentive bonus, malpractice, relocation, house hunting trip, health, dental, vision, 403(b) w/ contribution from PHS 457(b), short & long term disability, CME allowance, etc. Albuquerque thrives as New Mexico’s largest metropolitan center with a population of 700,000. Albuquerque has been listed as one of the best places to live in the United States by Newsweek, U.S. News & World Report, Money and Entrepreneur Magazines! Albuquerque is considered a destination city for most types of outdoor activities with 310 days of sunshine. A truly diverse and multicultural city, Albuquerque offers you and your family a great variety of activities and entertainment including national theater productions, sporting events, golf courses ranked among the best in the country, the largest hot air balloon festival in the US, American Indian Cultural activities and much more.

As a healthcare leader, we have opportunities. For a wide range of options, talk with a team that can offe ff r a wide range of opportunities. We W are one of the nation’s leading operators of general, acute-care hospitals. Our affiliates operate more than 200 hospitals in 29 stat a es and these locat a ions could provide ideal env n ironments fo f r your profe f ssional success. Comp m ensation packag ages may a include: • Flexible and generous start-up incentives • Medical education debt assistance • Va V rious practice typ y es

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GASTROENTEROLOGIST Gundersen Health System in La Crosse, Wisconsin is seeking a BC/BE Gastroenterologist to join its established medical team.

Practice in our state-off the-art Endoscopy Center and modern outpatient clinic. Outreach services are provided at our satellite clinics located within an easy drive from La Crosse. In addition, you will have opportunities fo f r clinical research and will be actively involved in teaching our Surgical, Transitional, and Internal Medicine residents. Yo Y u’ll join a physician-led, not-fo f r-profit health system with a top-ranked teaching hospital and one of the largest multi-specialty group practices with about 700 physicians and associate medical staff. ff Visit gundersenhealth.org/MedCareers Send CV to Kalah Haug, Medical Staff Recruitment, Gundersen Health System, 1900 South Ave., CO3-OO8, La Crosse, WI 54601 or call (608)775-1005.

EUS Gastroenterologist Opportunity We seek a BE/BC Gastroenterologist to join our collegial group. Provide a full spectrum of gastroenterology care to patients both in the hospital and through outpatient procedures. • 50% EUS and 50% General Gastroenterology • Call 1:5 • State-of-the-art cancer center nationally recognized for clinical excellence • Region’s tertiary referral center • EMR • Research opportunities

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

Ultrasound’s Role in Diagnosing IBS Becomes Clearer Preliminary study finds technology effective at distinguishing types of bowel disease

ltrasound does a lot of things well, from detecting breast cancer to determining the sex of unborn babies. Differentiating forms of bowel disease? Not so much. Or so the conventional wisdom holds. But Canadian researchers are revisiting the previously dismissed possibility that ultrasound can be used to distinguish diarrhea-predominant irritable bowel syndrome (IBS-D) from inflammatory bowel disease (IBD). In a study of patients with diarrhea, bloating and abdominal pain— symptoms common to both IBS-D and IBD—the investigators said they ruled out an inflammatory cause in 97% of cases using ultrasound alone.

“I think ultrasound can be a very useful way of obviating the need for more costly and invasive endoscopy in patients who do not have inflammation and therefore likely do not have IBD,” said senior investigator Kerri Novak, MD, clinical assistant professor in the Division of Gastroenterology in the University of Calgary’s Department of Medicine, and medical lead of quality assurance and imaging in IBD at the university’s Inflammatory Bowel Disease Clinic, in Calgary, Alberta. Since the 1980s, “essentially all consensus statements have recommended that clinicians not use ultrasound for the diagnosis of IBS, in light of studies showing it

greater than 35 kg/m2, the quality of ultrasound imaging was too poor to interpret, Dr. Novak said. A procedure that can filter out IBS patients who do not require more costly endoscopic procedures is an attractive prospect, Dr. Lacy said—and it might already exist. A recent meta-analysis found that C-reactive protein (CRP) of 0.5 mg/L or less, or fecal calprotectin of not more than 40 mcg/g are more than 99% accurate in ruling out IBD in patients with suspected IBS-D ((Am J Gastroenterol 2015;110:444-454). “Not only are these two markers very accurate and noninvasive, they are also pretty cheap,” Dr. Lacy added. William Chey, MD, professor of medicine at the

‘I think ultrasound can be a very useful way of obviating the need for more costly and invasive endoscopy in patients who do not have inflammation and therefore likely do not have IBD.’ —Kerri Novak, MD

Table. Concordance Between Ultrasound and Endoscopic Visualization

Figure 1. Normal colon with haustra, ileum and jejunum.

Diagnosis

Ultrasounda

Ileo-Colonoscopyb

IBS-D (n=30)

No inflammation

IBD (n=4)

One patient no inflammation

All patients had inflammation

Microscopic colitis (n=4)

No inflammation seen

Celiac disease (n=1)

No inflammation seen

Small bowel tumor (n=1)

Mass visualized

IBD, inflammatory bowel disease; IBS-D, irritable bowel syndrome with diarrhea a Sole criterion for inflammation using ultrasound: bowel wall thickness >4 mm. b Visualization without biopsy.

Figure 2. Ultrasound image of a thickened small bowel.

Figure 3. Ultrasound image of a bowel complication.

did not have utility for this indication,” said Brian Lacy, MD, PhD, professor of medicine and chief of the Section of Gastroenterology and Hepatology at the Geisel School of Medicine at Dartmouth-Hitchcock Medical Center in Lebanon, N.H. “But perhaps with advances in ultrasound technology since then, and if it is reserved for IBS-D patients, it may prove useful,” said Dr. Lacy, who was not involved in the study. Dr. Novak, who presented her team’s findings at the 2015 Canadian Digestive Disease Week (abstract 38), said she and her colleagues used ultrasound to document bowel wall thickness, the presence of mesenteric fat, lymph nodes and blood flow on color Doppler, as well as the presence of strictures or fistulae, in 60 patients presenting to the clinic with the triad of symptoms common to both IBS-D and IBD (Figures 1-3). All study participants also underwent ileo-colonoscopy within three months of ultrasound to further evaluate and confirm the presence or absence of inflammation. According to Dr. Novak, preliminary data from 41 patients indicated that a bowel wall thicker than 4 mm was roughly 86% sensitive in identifying colonic, ileal or small bowel inflammation and approximately 91% specific in ruling out inflammation (Table). The positive predictive value of the single criterion was 66.7% and the negative predictive value was 97%, she reported. In one patient with a body mass index

University of Michigan Health System, in Ann Arbor, and co-director of the Michigan Bowel Control Program, was senior investigator of the study examining the accuracy of CRP and fecal calprotectin, as well as other biomarkers of inflammation. Ultrasound would have to prove superior to those biomarkers before securing a spot in the armamentarium for IBS-D diagnosis, he said. “If CRP and fecal calprotectin are more accurate than ultrasound, there would be no reason to conduct ultrasound,” Dr. Chey said. “However, if its utility is validated in further studies, having ultrasound as another noninvasive test would be a valuable addition, and these authors should be congratulated for raising this possibility.” Dr. Novak said her team is planning to examine the added accuracy of combining ultrasound with fecal calprotectin testing to exclude or detect inflammation in more patients with suspected IBS-D. Dr. Chey added that even if more research confirms the accuracy of ultrasound, widespread use of ultrasound for this indication could be hampered because its accuracy hinges on an operator’s level of expertise. In contrast, he said, objective markers like CRP and fecal calprotectin are not associated with that problem. —David Wild Dr. Chey has served as a consultant to, and received research funding from Prometheus Laboratories. Drs. Novak and Lacy reported no relevant financial conflicts of interest.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

Severely Obese Subgroup Fares Worse After Bariatric Surgery, Study Shows Upper BMI threshold found; experts urge caution in interpreting data

ike several other studies before, a paper published recently in Annals of Surgery reported that bariatric surgery significantly increases life expectancy in obese individuals. However, this analysis also showed that a small subgroup of patients will have a

shorter life expectancy after undergoing a bariatric procedure for weight loss. Adults with a body mass index (BMI) greater than 60 kg/m2 who also have diabetes experience a reduction in life expectancy after bariatric surgery, according to the study.

“For most severely obese patients with diabetes, bariatric surgery seems to improve life expectancy; however, surgery may reduce life expectancy for the super obese with BMIs over 62 kg/m2,” wrote the authors, led by Daniel P. Schauer, MD, MSc, assistant professor of internal

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medicine at the University of Cincinnati College of Medicine, in the report published online in February ((Ann Surg 2015; doi: 10.1097/SLA.0000000000000907). The team of surgeons, internal medicine physicians and clinical researchers created a decision-analytic model to estimate the balance between treatment risks and benefits for severely obese patients with diabetes. They used data from three large cohorts: 159,000 severely obese diabetic patients, including 4,185 who underwent bariatric surgery, from three HMO Research Network sites; 23,000 patients from the Nationwide Inpatient Sample; and 18,000 patients from the National Health Interview Survey linked to the National Death Index.

Experts in bariatric surgery and bariatric medicine say the study raises questions about bariatric surgery in these severely obese patients, but does not show conclusively that there is no survival

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benefit.

Analysis showed that the vast majority of severely obese diabetic patients live longer after bariatric surgery than otherwise expected. According to the model, a 45-year-old woman with diabetes and a BMI of 45 kg/m2 gained an additional 6.7 years of life expectancy with bariatric surgery (38.4 years versus 31.7 years without surgery). However, as BMI increased, the gain in life expectancy decreased. When BMI levels reached 60 and greater, bariatric surgery was associated with a net loss in life expectancy. “At [that] point, no surgery is the preferred strategy,” the researchers wrote. Similar results were seen for men and women in all age groups. The study did not examine race. Experts in bariatric surgery and bariatric medicine say the study raises questions about bariatric surgery in these severely obese patients, but does not show conclusively that there is no survival benefit. “This statistical decision-making model raises some questions about the mortality benefit of bariatric surgery in

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2015

this high-BMI group of patients, but should not deter patients in this group from seeking bariatric surgery. Similarly, [these] data should not be used by bariatric surgeons to make individual clinical decisions with patients in this high-BMI group,” said Stacy Brethauer, MD, staff surgeon at the Bariatric and Metabolic Institute at the Cleveland Clinic, in Ohio. “The best we can say at this point is that it is uncertain what the survival benefit will be for this group of patients, since it hasn’t been adequately studied in a prospective clinical trial.” Dr. Brethauer, who performs bariatric surgery in patients with BMI greater than 60, said the benefits of surgery “far exceed” the risks, even in severely obese patients. “There are benefits to patients in terms of diabetes control and other comorbidities that weren’t examined in this study.” Oliver Varban, MD, director of the Adult Bariatric Surgery Program at the University of Michigan Health System in Ann Arbor, said the study findings are contrary to what he expected. “One would expect that patients with a higher BMI would have the most benefit from successful weight loss after bariatric surgery.” The results of the study may be different if the analysis were repeated today, he noted. Bariatric surgery changed during the study’s timeline. Most bariatric procedures are now performed laparoscopically, resulting in fewer complications and deaths, and shorter hospital stays. Sleeve gastrectomy is performed more often, and gastric banding has fallen out of favor. Instead of deterring patients from bariatric surgery, the study results should encourage patients to undergo surgery earlier in the disease process and before their BMI reaches 60, Dr. Varban said. “Patients with a BMI over 60 may lose a substantial amount of weight [more than 100 lb] after bariatric surgery but still be considered morbidly obese, in which case they may not achieve all of the benefits from surgery because their comorbidities remain. In this respect, I think it is important to offer bariatric surgery as a weight loss intervention for patients at an earlier stage [BMI 35-45], before their BMI increases to an unmanageable level.” In an interview, Dr. Schauer said it is unclear why diabetic patients with a BMI greater than 60, who represent less than 3% of the bariatric surgery patients in national databases sampled, may experience a decrease in life expectancy after surgery. “There are several theories but until more research is done, the reason remains unknown. It may be that the super obese, while losing a large proportion of their

excess weight, are less likely to lose enough to be classified as overweight or obese. They may have a longer duration of diabetes and are less likely to have remission after surgery.” The investigators noted that diabetic patients with a BMI greater than 60 kg/ m2 may still reap benefits from surgery, such as improved quality of life and reduced burden of obesity-associated diseases. These measures were not included in the model. —Christina Frangou

At a Glance •

Researchers used data from three large cohorts of patients.

•

The vast majority of patients live longer after bariatric surgery.

•

As body mass index increased, gain in life expectancy decreased.

•

A body mass index greater than 60 kg/m2 was associated with a loss in life expectancy.

•

Results may be different if analysis were reported today due to increased use of laparoscopy and changes in surgical approaches.

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