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Volume 64, Number 2 • February 2013

H E P A T O L O G Y

Souped-Up IFN Could Improve HCV Treatment

I N

F O C U S

Studies Point to Advent of IFN-Free ee Regimens for Hepatitis C Infection New Treatment Strategies Could Bring ‘Many More Cures’

BY KATE O’ROURKE BOSTON—A novel interferon, peginterferon lambda1a (Lambda, Bristol-Myers Squibb), may improve the treatment of patients with hepatitis C virus (HCV) infection, according to results from the Phase IIb EMERGE clinical trial. see Lambda, page 14

Real-World Use Of HCV DAAs Differs From Clinical Trials BY KATE O’ROURKE BOSTON—Discontinuation rates with boceprevir (Victrelis, Merck & Co.) and telaprevir (Incivek, Vertex Pharmaceuticals) are much higher in the real-world setting than in the clinical trials that led to the drugs’ approvals. see Real-World, page 33

BY KATE O’ROURKE BOSTON—Enthusiasm is growing for the various interferon (IFN)-free therapies on the horizon for patients with hepatitis C virus (HCV) infection. At the recent annual meeting of the American Association for the Study of Liver Diseases (AASLD), The Liver Meeting 2012, four of the six late-breaking abstracts and a slew of other studies discussed new oral regimens that can be used to achieve high rates of sustained virologic response (SVR) in a variety of HCV patient cohorts, including null responders.

“We can see a light at the end of the tunnel,” said Guadalupe Garcia-Tsao, MD, professor of medicine at Yale University, New Haven, Conn., and chief of see IFN-Free, page 16

Experts’ Picks I N S I D E

Best of The Liver Meeting

Hepatic Encephalopathy Explored

COMPILED AND WRITTEN BY DAVID WILD

In New Film, Clinical Studies ...................page 30

Gastroenterology & Endoscopy News asked several experts to select theeir favorite abstracts from The Liver Meeting 2012, the annual meeting of the American Association for the Study of Liver Diseases. Following is a collection n of their selections and comments that reflect the varied interests of the experrts who we interviewed. see Best of AASLD, page 8

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Vol. 64, No. 2 MEDICAL ADVISORY BOARD MANOOP S. BHUTANI, MD

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GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2013

A Keynesian View of Health Care Jon C. White, MD Professor of Surgery George Washington University Chief of Surgery VA Medical Center Washington, D.C. When people ask me my thoughts on health care, I tell them I am a Keynesian. John Maynard Keynes (18831946), a British economist, was the most influential economist in the United States in the early to mid-20th century when, coincidentally, medicine began its ascent from the Dark Ages. Most importantly, his philosophy of economics comports with my observations of the practice of medicine. Keynes wrote: “The theory of economics does not furnish a body of settled conclusions immediately applicable to policy. It is a method rather than a doctrine, an apparatus of the mind, a technique of thinking, which helps its possessors to draw correct conclusions.” During my 30-year career in medicine, I have come to think about medicine in the same way. Medicine has very few settled conclusions. At its best, it is a method and a way of thinking that helps practitioners draw the right conclusions about the information at hand.

Medicine: A Method, not a Doctrine Take the story of sepsis, for example. Just over a century ago, the concept of microorganisms as pathogens was first proposed and then confirmed. Treatment started with public health measures to control their spread. Later came the antimicrobials to eradicate the offending organisms and then measures to treat the physiologic consequences of sepsis, such as fluid resuscitation and vasoactive agents. Next there were strategies aimed at altering or neutralizing the cellular consequences of infection and, more recently, we are taking the battle to both the molecular and genetic levels. What is the next frontier? Will it be nanotechnology or maybe something that we haven’t yet considered? The overriding lesson learned by our changing approach to sepsis is that medical science is not an established and immutable collection of facts that we learn to master and continuously apply. Rather, like Keynes’ concept of economics, it is the method that we use to approach a problem. We make intelligent observations that guide our decisions. These decisions and the actions they provoke are appropriate until they are proven incorrect or something better comes along and then they should be abandoned as enthusiastically as they were initially accepted. I am reminded that Florence Nightingale first championed large open wards to improve ventilation for hospitalized patients until it was determined that patients, especially those with communicable diseases, should be isolated when possible. Aggressive fluid resuscitation of

trauma victims to restore vital signs to normal levels was practiced indiscriminately until it was recognized that “shock lung” might be made worse by this practice. Now, more judicious fluid resuscitation is recommended. There are certainly many more examples of the practice of medicine being an evolving science that is always changing. The only thing that stays the same is the process of making careful observations and then drawing conclusions about which treatments are likely to be effective. The practice of medicine is more than a static body of information with established solutions; it is a method.

Financing Health Care Delivery How about providing health care to our 300 million citizens? I think we can apply this same Keynesian philosophy to national health care delivery. There is no static right way to deliver care because the industry is constantly evolving and its objective—maintaining the health of our nation—is a moving target. Health care needs are determined by a set of shifting variables including an aging population; more sedentary lifestyles; increasing national obesity; the explosion of technology; and newfound interests such as patient safety, quality management and infection control. Many of these problems are being addressed by people and programs that didn’t exist 20 years ago, such as minimally invasive and robotic technology, bariatric surgery/medicine, patient safety offices, quality management departments and infection control committees.

Health Care Challenges Still Unanswered Letter to the Editor

Re: “Gastroenterologists Discuss Challenges, Changes, Future of GI Health Care,” by Monica J. Smith. Gastroenterology & Endoscopy Newss October 2012;63:1,50,52.

I’d like to raise the same points I raised at last year’s meeting [2012 GI Roundtable, March 30-31, Knoxville, Tenn.] for this year’s meeting [2013 GI Roundtable, March 15-17, Boston; giroundtable.com]:

an ACG Visit d AA bo us SL oth at D bo #1 oth 614 #1 13

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

‘Astonishing’ Data on Metformin for HCC By Christina Frangou San Diego—One of the most widely used diabetes drugs in the world appears to have an unexpected secondary benefit: reducing the risk for hepatocellular carcinoma (HCC) by more than 50%, according to two new studies. Results from an American case–control study and a see Metformin, page 26

First Guideline on NAFLD Published By Christina Frangou

Studies Attempt To Deﬁne Patient Preferences for CRC Screening By Caroline Helwick Despite its clear benefits, colorectal cancer (CRC) screening rates in the United States have stalled at around 50% of those eligible for screening. Acceptance of screening recommendations might be enhanced if certain barriers could be overcome. Some believe that computed tomographic colonography (CTC) might be one way to improve adherence to screening recommendations. This topic has been the aim of several recent clinical research surveys. What do these surveys reveal? Are they accurate reflections of what patients truly desire? And why bother asking: Does patient preference really matter? “The patient’s input and preferences have to be regarded as an absolutely central component of highquality care,” said David Weinberg, MD, MSc, chairman and professor of medicine at Fox Chase Cancer Center in Philadelphia, who spoke on the subject at

1. I haven’t seen a quality measure yet that would help a central authority make decisions. 2. There is no reason to accept draconian regulations from government that increase costs and decrease funds for providing excellent care. 3. Dumbing down our procedural excellence by using lesser trained nurses, physician assistants and non-gastroenterologist physicians is antithetical to our mission as high-quality specialists. 4. Fee-for-service at a fair price is an excellent system, especially when mandates for electronic records—which are not secure or efficient—may be eliminated. 5. Ditto for supposed quality reporting to government. 6. Capitation of populations is a losing strategy, for both gastroenterologists and patients. 7. Finally, think outside the box. Many people will want prompt and efficient care for a fair price outside of their insurance (e.g., Canada, etc.). I will leave it to unproven accountable care organizations and hospitalaffiliated groups to keep struggling with the never-ending demands for lower fees and ever larger reporting demands. Ronald Feldman, MD Gastroenterologist Escondido, Calif. Jan. 6, 2013 Three leading American gastroenterology societies have published a new guideline on the diagnosis and management of non-alcoholic fatty liver disease (NAFLD). Prompted by the fact that physicians are seeing a growing number of patients with the disease, this is the first time that any of these professional societies have developed

the 2012 Digestive Disease Week meeting in a lecture entitled, “What Will Be Competing with Colonoscopy in 5 years?” “Clearly, patients who are well versed at an appropriate level, understand their treatment options and see Patient Preferences, page 7

see NAFLD Guideline, page 28

Dynamic health care speakers sharing with GI leaders the latest on reform, change and the future of gastroenterology.

I N S I D E

GI Roundtable Rou und 2012

Gastroent Gast oe enterologists e Discuss Challenges, Chan nges, Future Fu of GI Health Care Compiled and written by Monica J. Smith

Knoxville, Tenn.—The GI Roundtable conference evolved as a collaboration between Bergein Overholt, MD, of Gastrointestinal Associates in Knoxville, Tenn., and Klaus Mergener, MD, PhD, MBA, of Digestive Health Specialists in Tacoma,

EXPERT’S PICKS Best of Digestive Disease Week (DDW): Inﬂammatory Bowel Disease (IBD)

Ellen J. Scherl, MD, provides an overview of IBD research presented at the DDW meeting Ellen J. Scherl, ............................................ page 10 MD

Complications of Biologic Therapy for IBD

Four IBD experts discuss common risks and complications associated with anti-TNF therapy for IBD ............................................ page 14

see GI Roundtable, page 50

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Dealing with

Disruptive Change Keynote Speakers X X X

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Conference Directors X X

Klaus Mergener, MD, PhD, MBA Bergein F. Overholt, MD

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2013

Consequently, any plan to finance the health care industry that was conceived as recently as 20 years ago is no longer relevant. The initial strategies to finance this quickly evolving enterprise today seem almost quaint and the estimates of needed resources are woefully inadequate. This is a new industry that requires a new approach. The old paradigms of fee-for-service or socialized medicine have been tried and found to be inadequate for the job at hand. We are beyond them now and new strategies need to be designed. There are many in the planning phase, such as hybridized capitalistic/socialized systems, capitated plans with carve-outs, personal health insurance models, models employing salaried workers with incentive bonuses and so on. There are many new ideas. What seems clear is that we should never go back to the simple models of financing, such as pure fee-for-service or entirely socialized plans. They are as outdated and irrelevant today as the open wards of Florence Nightingale. The practice of medicine is changing rapidly and health care financing must continue to evolve to meet the demands of the industry.

Any plan to finance the health care industry that was conceived as recently as 20 years ago is no longer relevant.

Government Intervention in Economic Policy The other way in which I count myself as a medical Keynesian is regarding his thoughts on government intervention. Keynes argued that “private-sector decisions about the economy sometimes lead to bad macroeconomic outcomes for the economy.” He advocated for active policy responses by the government including monetary policy actions by a central bank and fiscal policy actions by the government. He recognized the competing needs caused by inflation on one hand and depression on the other hand. They occurred in cycles and Keynes tried to dampen the amplitude of these cycles by monetary policy. He would encourage deficit spending in a recession or depression but taxation and spending cuts during periods of inflation. Keynes’ ideas of government intervention left him open to the criticism that he was a populist or socialist. Nothing could be further from the truth. Keynes was a Cambridge University don, married to a ballerina and a member of the Bloomsbury Group, a collection of elite British writers and thinkers. He was a member of the landed gentry and a true classic Adam Smith capitalist who proposed his ideas to save capitalism rather than oppose it. I think that during the difficult years of the U.S. depression, when socialism or communism were being considered as viable alternatives to capitalism, it was interventional policies such as those proposed by Keynes that saved our system.

Recommendations for Regulation In Health Care In medicine today, we are again navigating some very dangerous straits. On one hand, we have a workforce shortage, underserved populations and problems that require more spending, whereas on the other hand, we have tremendous inflation, which suggests that we should tighten our belts. I think that if Keynes were making policy decisions today he would suggest that government intervention is needed. I would agree with him. How can government intervention help? Here are some suggestions: 1. Tort reform is a good place to start. I find it somewhat hypocritical that many of the physicians who think that government should be out of our lives, welcome its intervention with tort reform to protect us from predatory lawyers. I am one of the many who think that laws capping noneconomic or punitive damages should be adopted in all states now. Eventually, I

woould like to see complete reorganizattion of the tort system to one in which a governmentrun n, medical/legal board ard would adjudiadjudi cate all claims. I don’t think an unregulated legal industry will make these corrections on its own, and if we are forced to confront them mano a manoo they are far more powerful than we are. We need the government in our corner. 2. Medicare/Medicaid currently accounts for 35% of all health care spending. Much of that is for working or retired seniors who can afford the premiums without government assistance. Some kind of means testing seems to be in order to bend the cost curve. The American Association of Retired Persons and lobbies sympathetic to the elderly are powerful, and the only entity large enough to face off against them is the federal government. 3. The U.S. Preventive Services Task Force is an organization funded by the Department of Health and Human Services that is tasked with determining the utility of health care measures that we are now purchasing. Their shocking finding is that 15% to 30% of Medicare expenditures are for diagnostics or treatments that are of no proven benefit or are even harmful. This situation requires some difficult decisions that, with the current absence of direction from our profession, will have to be made by the government. 4. It is well known that approximately 30% of Medicare payments cover the cost of care for people in the last year of life, much in the last few months. Some of this spending is understandable because one’s terminal illness is usually the most significant (and expensive) illness of one’s life. It is still an enormous expense, and there are strategies to decrease its impact on the health care budget such as a) increased use of advance directives, b) promoting hospice care and c) withholding futile care. It will take courage to stand up and address this situation and brave the politically inspired rhetoric and the shrill claims of creating death panels, pulling the plug on Granny and so forth. The people who

The old paradigms of fee-for-service or socialized medicine have been tried and found to be inadequate for the job at hand. We are beyond them now and new strategies need to be designed. are best positioned to do this are physicians working closely with the government to set up some medically sound ground rules. These are only a few of the many ways in which the government can and, in my opinion, should now intervene in our health care system. I do believe in the core principle that government should be kept as small as possible and that its role should be to provide services that no one else can provide, such as national defense. I think that regulating, not owning, the health care industry is one of those tasks. It was the government that adopted regulations from the Flexner Report that made allopathic medicine a respected profession. A government-run public school system started Blue Cross/Blue Shield, the first medical insurance company, which has become the engine that drives our industry. Government stepped in, in 1965, with Medicare and Medicaid to increase access to health care for our most vulnerable citizens. More recently, it has helped to both curb health care inflation (e.g., resource-based relative value scales and diagnosisrelated groups) and extend coverage (e.g., Medicare parts C and D). The government has paid for resident training, built hospitals, supported health care research and provided tax incentives for purchasing health care. Government has always been an important partner to the health care industry and, like a proactive Keynesian economist, it has intervened in times of crisis. Keynes’ economic philosophy was to support capitalism not to destroy it. Medicine, these days, seems to be on a path of self-destruction, and I think if Keynes were still with us, he would conclude that we need a proactive government to protect us from our own folly. ■

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2013

Best of The Liver Meeting 2012 continued from page 1

Raymond Chung, MD Associate Professor Department of Medicine Harvard Medical School Director of Hepatology Massachusetts General Hospital Boston, Massachusetts

LB-1.

A 12-Week InterferonFree Treatment Regimen with ABT-450/r, ABT-267, ABT-333 and Ribavirin Achieves SVR12 Rates (Observed Data) of 99% in Treatment-Naïve Patients with 93% in Prior Null Responders with HCV Genotype 1 Infection (Kowdley KV et al) In this trial, 438 noncirrhotic, treatment-naive patients with hepatitis C virus (HCV) genotype (GT)-1 infection and 133 null responders to pegylated interferon (PEG-IFN)–ribavirin (RBV) combination treatment underwent eight, 12 or 24 weeks of treatment with ABT-450, an HCV protease inhibitor (PI), at 100 or 200 mg per day. ABT-450 is dosed along with ritonavir 100 mg per day. Patients also received, alone or in combination, the NS5A inhibitor ABT-267 25 mg per day and the non-nucleoside NS5B inhibitor ABT-333 400 mg twice daily. All participants also received weight-based dosing of RBV. The average baseline HCV RNA level among the patients was approximately 6.5 log10 IU/mL. Seventytwo percent of treatment-naive subjects and 96% of prior null responders had the interleukin 28B (IL28B) non-CC C genotype at baseline and 66% of patients had HCV GT1a. Findings shared at the meeting included data from 79 treatment-naive subjects and 45 null responders in the eight- and 12-week treatment arms. Results showed that 99% and 93% of treatment-naive and prior null responders, respectively, achieved sustained virologic response (SVR) at week 4. Preliminary data revealed the same rates of SVR at week 12. Three prior null responders experienced virologic breakthrough and one treatment-naive patient relapsed. Subgroup analyses showed that prior null responders with HCV GT1a had the lowest SVR rate at week 12, at 89%, followed by those with the IL28B B non-CC C genotype, 92% of whom achieved SVR at week 12. In all other subgroups, SVR rates at week 12 were 98% or higher. Common adverse events (AEs) included fatigue and headache, and five patients experienced serious AEs, with four consequently discontinuing treatment. According to the investigators, only one of these severe AEs, arthralgia, was possibly related to a study medication. Dr. Chung In this study, three direct-acting antiviral agents (DAAs)—none of which was a nucleotide polymerase inhibitor—in conjunction with RBV, produced high rates of SVR in an IFN-sparing manner. Remarkably, this study demonstrates that these high SVR rates also can be accomplished in a traditionally difficult-to-treat group, namely prior null responders to PEG–RBV.

Collectively, these studies show that there are several roads to the same destination. These findings give us great hope that IFN-free regimens will have truly broad applicability.

LB-2.

High Rate of Sustained Virologic Response with the All-Oral Combination of Daclatasvir (NS5A Inhibitor) Plus Sofosbuvir (Nucleotide NS5B Inhibitor), with or without Ribavirin, in TreatmenttNaïve Patients Chronically Infected with HCV Genotype 1, 2 or 3 (Sulkowski MS et al) Researchers in the United States and Puerto Rico randomized 44 patients with noncirrhotic HCV GT1 inffection and 44 patients with noncirrhotic HCV GT2/3 infection to undergo treatment with one of three regimens that included sofosbuvir (SOF), a nucleotide NS5B inhibitor: One group received SOF 400 mg daily for seven days, followed by SOF plus daclatasvir (DCV) 60 mg daily for 23 weeks; a second group underwent 24 weeks of treatment with SOF/DCV; and a third group received 24 weeks of SOF/DCV plus RBV, dosed at 1,000 to 1,200 mg daily in HCV GT1 patients and at 800 mg daily in HCV GT2/3 patients. Most HCV GT1 participants had GT1a HCV. Baseline HCV RNA level in all groups was at least 6.5 log10 IU/mL

‘These findings demonstrate profoundly high rates of virologic response in patients with HCV GT1, GT2 and GT3 infection using two potent DAAs, one of which, sofosbuvir, has a very high barrier to resistance.’ —Raymond Chung, MD All patients achieved a rapid virologic response (RVR) after four weeks of treatment. All HCV GT1 patients and 86% to 88% of HCV GT2/3 patients achieved SVR at weeks 4 and 12. One HCV GT3 patient relapsed four weeks following treatment and was found to have a preexisting NS5A-A30K polymorphism. Preliminary data from patients followed for 24 weeks post-treatment showed SVR rates of 97.5% and 95% at week 24 in HCV GT1 and HCV GT2/3 patients, respectively. One patient with HCV GT1a and IL28B CT-genotype T in one of the non-RBV treatment arms relapsed between weeks 12 and 24 after treatment cessation. There were no differences in treatment response based on HCV GT1 subtype, IL28B B genotype or use of RBV. Fatigue, headache and nausea occurred in more than 20% of patients, and some individuals receiving RBV experienced grade 3/4 anemia. Dr. Chung These findings demonstrate profoundly high rates of virologic response in patients with HCV GT1, GT2 and GT3 infection using two potent DAAs, one of which, SOF, has a very high barrier to resistance. The finding

of activity against multiple HCV genotypes reinforces the pangenotypic nature of this class of agents.

LB-3.

An Interferon-Free, Ribavirin-Free 12-week Regimen of Daclatasvir (DCV), Asunaprevir (ASV), and BMS-791325 Yielded SVR4 of 94% in Treatment-Naïve Patients with Genotype (GT) 1 Chronic Hepatitis C Virus (HCV) Infection (Everson GT et al) In this international, multicenter, Phase IIa open-label study, 32 treatment-naive, noncirrhotic patients with chronic HCV GT1 infection were randomly assigned to receive 12 or 24 weeks of treatment with asunaprevir (ASV), an NS3 PI, 200 mg twice daily, along with DCV 60 mg daily and BMS-791325, a selective non-nucleoside NS5B polymerase inhibitor, at 75 mg twice daily. Another 15 patients each underwent the same regimen but received BMS-791325 150 mg twice daily instead; data from this higher-dose treatment arm was not presented at the meeting. Patients were a median of 48 years of age, 75% were white and 28% had the IL28B B non-CC C genotype mutation. Mean HCV RNA level at baseline was 6.26 log10 IU/mL. Results showed 100% of patients in both groups receiving BMS-791325 75 mg twice daily achieved RVR at week 4, and 88% and 94% of patients in the 12- and 24-week groups, respectively, had undetectable HCV RNA at week 12. Ninety-four percent of both groups achieved SVR at weeks 4 and 12 after treatment cessation. There were no virologic breakthroughs or relapses. The most common AEs included headache, diarrhea and asthenia. None of the patients experienced grade 3/4 liver enzyme elevations, and no patients required treatment discontinuation due to AEs. Dr. Chung This regimen is striking because it shows that the use of three distinct classes of HCV inhibitors, none of which has particularly high barrier to resistance, is capable of achieving high rates of SVR in both an IFN- and RBVsparing manner. Dr. Chung has received research funding from Gilead Sciences, Mass Biologic and Merck & Co., and has served as a consultant for Enanta.

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2013

Patrick S. Kamath, MD Professor of Medicine Department of Gastroenterology and Hepatology Mayo Clinic School of Medicine Rochester, Minnesota

A-01.

Outcomes and Complications of Intracranial Pressure Monitoring in Acute Liver Support: A Retrospective Cohort Study (Karvellas CJ et al) The benefits of intracranial pressure (ICP) monitoring of acute liver failure (ALF) patients with grade 3/4 encephalopathy, who are at risk for intracranial hypertension (ICH), are controversial. In this study, researchers retrospectively compared rates of ICH in 143 patients with ALF with grade 3/4 encephalopathy who underwent ICP monitoring and 487 patients who did not. Patients had been enrolled in the prospective U.S. Acute Liver Study Group between 2004 and 2011. The most common cause of ALF was acetaminophen toxicity. Eighty-five percent of monitored patients received their ICP monitoring devices within 24 hours of study enrollment.

‘Intracranial pressure monitoring is associated with significantly increased mortality

monitored patients developed ICH, defined as ICP above 25 mm Hg. Moreover, 43% of patients with ICH died during the study period compared with 23% of those without ICH (P=0.049). P Among a subgroup of four monitored patients who developed hemorrhagic complications, three died. Overall 21-day mortality rates were similar between the monitored and nonmonitored patients (33% vs. 37%, respectively), and mortality rates remained unchanged in a subgroup analysis including only non-transplant patients.

Dr. Kamath Cerebral edema is a feature of ALF and is a cause of mortality in these patients. However, placement of ICP monitors in patients with profound coagulopathy may be associated with risks for bleeding and infection. This study addresses the safety and efficacy of placing ICP monitors in patients with ALF. This is a retrospective study, and it is unclear whether ICP monitors were placed in selected patients who were either sicker or more likely to undergo a liver transplantation. It is also unclear whether

“After an episode of [overt HE], prophylactic therapy with lactulose or rifaximin is recommended for an indeﬁnite period of time or until liver transplantation.”

acute liver failure. These results

73% of recurrences among lactulose patients result in hospitalization 2

suggest intracranial pressure

Xifaxan 550 mg reduces the risk of HE-related hospitalizations by 50%3†‡

—Patrick S. Kamath, MD

Compared with the control group, monitored patients were significantly younger, more likely to undergo renal replacement therapy and more likely to receive fresh frozen plasma. Also, significantly more monitored patients underwent ICH-directed therapies, including mannitol (43% vs. 13%), hypertonic saline (21% vs. 6%) and hypothermia (29% vs. 11%). Furthermore, 78% of monitored patients were subsequently listed for liver transplantation compared with 27% of control patients (P<0.001). During the study period, 51% of

see Best of AASLD, page 10

OUT OF THE HOSPITAL DOESN’T MEAN OUT OF THE WOODS —Clinics in Liver Disease, February 20121

in this group of patients.’

ICP was used to “de-list” patients for liver transplantation and whether a standard management protocol was used for treatment of ALF. Nevertheless, the study shows that ICP monitoring affects treatment of ICH without reducing mortality rates in acetaminophen-related ALF. Moreover, ICP monitoring is associated with significantly increased mortality in non– acetaminophen-induced ALF. These results suggest ICP monitoring should not be used in this group of patients.

For overt HE* patients

in non–acetaminophen-induced

monitoring should not be used

The most common adverse reactions (≥12% incidence) in clinical trials with Xifaxan 550 mg were peripheral edema, nausea, dizziness, and fatigue.

Prescribe. Protect. Repeat.

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

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

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

www.Xifaxan550.com

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

Best of AASLD continued from page 9

D-01.

Randomized Controlled Phase 2 Study with Tivantinib in Pre-Treated Hepatocellular Carcinoma (HCC): Efficacy, Safety and MET-Analysis (Borbath I et al) An earlier Phase I trial showed tivantinib, a selective oral inhibitor of the hepatocyte growth factor receptor MET,

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

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

is effective in treating hepatocellular carcinoma (HCC), either alone, in combination with or following treatment with sorafenib (Martell R et al. ASCO 2012. Abstract 4117). This study included 107 patients with Child-Pugh class A unresectable HCC who had received prior treatment with systemic therapy and had a prognostic score higher than 2. All patients underwent liver biopsy to determine the extent of MET expression on tumor cells. Seventy-one patients were randomized to receive treatment with tivantinib and

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

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

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

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

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

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

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

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

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

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2013

Number (%) of Patients

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

XIFAXAN Tablets 550 mg TWICE DAILY N = 140

Placebo N = 159

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

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

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

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

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

36 received placebo. The first 57 treatment recipients were administered tivantinib 360 mg twice daily but the dose was reduced to 240 mg twice daily in the remaining 14 patients after a significant number of recipients of the higher dose developed high-grade neutropenia. Baseline patient characteristics were similar in both the treatment and placebo groups. In an intent-to-treat analysis, the median time to tumor progression was 1.6 months in the treatment group compared with 1.4 months in the placebo group (hazard ratio [HR], 0.64; 90% confidence

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

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

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

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

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

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

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

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

interval [CI], 0.43-0.94; P P=0.04). The median time to tumor progression among patients with higher expression of MET on tumor cells was 2.7 months (HR, 0.43; P P=0.03). Median overall survival among patients with higher expression of MET was 7.2 months compared with 3.8 months among high MET expressers in the placebo group (HR, 0.38; P=0.01). P Individuals with high MET expression who did not receive treatment were 60% more likely to experience disease progression and 195% more likely to die compared with those with lower MET expression, the researchers found. AEs in tivantinib-treated patients with high MET expression included fatigue in 31.7% and asthenia in 27.3%. Tivantinib 240 mg twice daily was as effective as tivantinib 360 mg twice daily and was associated with a significantly lower incidence of high-grade neutropenia. Dr. Kamath Expression of MET, the receptor tyrosine kinase for hepatocyte growth factor, is often dysregulated in patients with HCC and correlates with progression of disease and poor outcome following hepatic resection for HCC. High MET expression is defined as 50% or more cells showing strong staining intensity in tumor biopsies. In this study, the group of patients who demonstrated high MET expression in tumor cells experienced the best response to tivantinib, an inhibitor of MET. Conversely, in patients with high MET expression who did not receive tivantinib, there was a significantly higher risk for disease progression and death. The association between MET expression and tumor progression—and MET inhibition and tumor nonprogression—was clearly demonstrated. Therefore, tivantinib use should be restricted to patients with HCC with high MET expression. Although biopsies are not required for diagnosis of HCC, this study suggests that biopsies may be required in the future for better choice of therapy.

S-07.

A Multicenter Study of Protease Inhibitor-Triple Therapy in HCVInfected Liver Transplant Recipients: Report from the CRUSH-C Group (Burton JR et al) This study examined the efficacy of triple therapy including PEG-IFN, RBV and an HCV PI in 61 consecutive liver transplant recipients with HCV GT1 infection. Most of the patients were male and approximately half had undergone prior treatment. Previous treatment led to no response in 31% of patients, partial response in 50% and initial treatment success but relapse in 19%. Ten percent of

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2013

patients had fibrosing cholestatic hepatitis and 43% had bridging cirrhosis or fibrosis. Triple therapy included telaprevir (TPV) in 92% of patients. Treatment was initiated a mean 33.6 months after transplantation (interquartile range [IQR], 16.7-64.3 months), included a median lead-in of 28 days with PEG-IFN–RBV prior to TPV initiation and continued for a median of 136 days, including the lead-in period. Concurrent treatments included cyclosporine in 62% of patients, tacrolimus in 27%, steroids in 30% and mycophenolate mofetil in 77%. Total HCV RNA load prior to TPV administration was a median 5.17 log10 IU/mL. HCV RNA levels fell below the limit of detection in 63% and 72% of patients at weeks 4 and 12, respectively. Median time to achieve undetectable levels of HCV RNA was 55 days after lead-in (IQR, 46-98 days) and 28 days after TPV initiation (IQR, 54-134 days). Eighteen percent of patients required hospitalization for treatment-related severe AEs. Two patients died during the treatment period, one due to sepsis and another due to renal failure. Treatment was discontinued in 6.5% of patients due to AEs. Thirty-seven percent of patients required one or more transfusions, and 33% experienced an increase in creatinine of at least 0.5 mg/dL. Dose reductions of PEG-IFN were required in 60% of patients and 46% of patients needed RBV dose reductions. Dr. Kamath Recurrence of HCV infection is invariable following liver transplantation and is associated with an accelerated course to cirrhosis and graft loss, and a less than satisfactory response to PEG-IFN–RBV therapy. Triple drug therapy with either TPV or boceprevir (BOC) in combination with PEG-IFN–RBV is associated with impressive SVR rates, on the order of 70% to 80% in non-transplant recipients with HCV GT1 infection. This study addresses the concern that because TPV and BOC are inhibitors of the cytochrome P450 CYP3A4/5 enzyme, both have significant interactions with drugs that either induce or require the same pathway. Thus, exposure to cyclosporine is increased 4.6-fold and tacrolimus exposure is increased 70-fold in patients receiving TPV or BOC. This study demonstrates that initial responses to triple drug therapy for HCV infections in patients who have undergone liver transplantation are promising, but close monitoring of patients and frequent adjustments of dosages of calcineurin inhibitors are required.

David Nelson, MD Associate Dean for Clinical Research Division of Gastroenterology, Hepatology and Nutrition University of Florida College of Medicine Gainesville, Florida

51.

Safety and Efficacy of Telaprevir or Boceprevir in Combination with Peginterferon Alfa/Ribavirin in 455 Cirrhotic Non Responders. Week 16 Analysis of the French Early Access Program (Hezode C et al) French investigators analyzed data from 455 HCV GT1 patients with ChildPugh A cirrhosis who were administered triple therapy with an HCV PI and PEGIFN–RBV as part of the French CUPIC (Compassionate Use of Protease Inhibitors in Cirrhotics) study. In one treatment

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arm, 296 patients underwent 12 weeks of treatment with TPV in combination with PEG-IFN alfa-2a plus RBV followed by 36 weeks of PEG-IFN–RBV; in a second arm, 159 individuals received four weeks of PEG-IFN alfa-2b plus RBV followed by 44 weeks of BOC in combination with PEG-IFN–RBV. An intent-to-treat analysis found that 51%, 79%, 78% and 71% of TPV recipients achieved undetectable HCV RNA at weeks 4, 8, 12 and 16 of treatment, respectively. HCV RNA below the limit see Best of AASLD, page 12

ASGE Endoscopy Unit Recognition Program ASGE’s Endoscopy Unit Recognition Program honors endoscopy units committed to the highest standards of quality and safety. It is the only national program recognizing quality and safety in the practice of endoscopy. > Gain recognition among healthcare professionals, public and private regulatory bod bodies, and patients as a unit dedicated to quality care > Prep pare to meet the changing expectation of public and private regulatory bodies > Promote improvement and create uniformity in your practice > Other marketing tools for promoting your recognition Certain eligibility criteria apply, including completion of the ASGE Quality Course, “Improving Quality and Safety in n your Endoscopy Unit,” by a representative of your unit within one year of program application. In 2013, ASGE will offer the course as follows: February 8, 2013 – San Francisco, CA June 8, 2013 – Philadelphia, PA September 19, 2013 – Las Vegas, NV at EndoFest® 2013 9LJLP]L Ä JH[L VM 9LJVNUP[PVU [V WYV\KS` KPZWSH` PU `V\Y LUKVZJVW` \UP[»Z VMÄ WYV\KS` ÄJL

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Dr. Kamath reported no conflicts of interest.

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54.

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of detection was achieved in 1%, 37%, 58% and 61% of BOC recipients at weeks 4, 8, 12 and 16, respectively. Serious AEs occurred in 48.6% of TPV recipients and 38.4% of BOC recipients, with 14.5% and 7.4% of patients, respectively, discontinuing treatment as a result. Two percent and 1.3% of TPV and BOC recipients, respectively, died because of treatment-related complications during treatment; 8.8% and 2.5% of TPV and BOC recipients, respectively, developed grade 3/4 infections, and 4.4% of patients in both groups experienced hepatic decompensation. Grade 3 rash occurred in 6.8% of TPV recipients and none of the BOC patients.

‘The benefit of the CUPIC study is that patients with advanced disease have been underrepresented in Phase III trials of protease inhibitors. Thus, these data provide important new safety and efficacy information.’ —David Nelson, MD Researchers found that approximately 10% of patients in both groups developed grade 3/4 anemia, and 56.8% and 66% of TPV and BOC recipients, respectively, required erythropoietin. Also, 15.2% and 10.7% of TPV and BOC recipients, respectively, required a transfusion. Approximately 4% of patients in both groups developed grade 3 neutropenia; grade 4 neutropenia occurred in 0.7% and 0.6% of the two groups. Grade 3/4 thrombopenia occurred in 1.3% of TPV patients and 0.6% of BOC recipients, with less than 2% requiring thrombopoietin. Five percent and 4.4% of TPV and BOC patients, respectively, required dose reductions in RBV. Dr. Nelson The CUPIC cohort study has received a lot of press regarding the high rates of AEs that have occurred in the trial. However, one must be cautious not to generalize these results to broader populations because the CUPIC study focused only on patients who had cirrhosis, many of whom had portal hypertension. The benefit of the CUPIC study is that patients with advanced disease have been underrepresented in Phase III trials of PIs. Thus, these data provide important new safety and efficacy information. My conclusion from this data is that the treatment of patients with cirrhosis should be undertaken with the expectation that patients will need to be followed very closely and will likely need significant management of AEs, anemia being the most common. However, the antiviral activity of the drugs used in this trial based on these interim results is quite impressive, with on-treatment viral negativity approaching 70% to 75%. Assuming relapse rates of 10% to 15%, the final results from CUPIC may demonstrate SVR rates in the 50% to 60% range for a very high-risk population. This level of treatment efficacy would very significantly reduce morbidity and mortality in this population. The high rate of AEs with these drugs, along with the equally high antiviral efficacy, highlights the need for physicians to discuss the risks and benefits of treatment with patients with advanced disease prior to initiating therapy with these regimens.

Telaprevir in Combination with Peginterferon Alfa-2a/Ribavirin in HCV/HIV Co-Infected Patients: SVR24 Final Study Results (Sulkowski M et al) This was a randomized, double-blind, placebo-controlled, parallel-group, Phase II trial of TPV in combination with PEG-IFN alfa-2a and RBV in 62 treatment-naive patients coinfected with HCV GT1 and HIV. In one group, seven patients received 12 weeks of treatment with TPV 750 mg every eight hours, PEGIFN 180 mcg weekly and RBV 800 mg daily, followed by 36 weeks of PEG-IFN–RBV; six patients received a placebo with PEG-IFN–RBV for 48 weeks. In a second study group, 16 patients received 12 weeks of the same TPV-based regimen, with a TPV dosage of 1,125 mg. These patients concurrently received efavirenz, tenofovir and emtricitabine during the first 12 weeks and PEG-IFN–RBV alone for the remaining 36 weeks of treatment. Eight patients received 48 weeks of treatment with the same regimen but were administered a placebo in place of TPV. In a third group, 15 participants received TPV 750 mg every eight hours with PEG-IFN–RBV and atazanavir/ ritonavir for 12 weeks, followed by 36 weeks of PEGIFN–RBV; eight patients received the same regimen with a placebo in place of TPV for 48 weeks. At least 81% of patients in all groups had baseline HCV RNA of at least 800,000 IU/mL. Mean CD4 counts were at least 562 cells/mL. RVR at week 4 occurred in 68% of all TPV recipients compared with none of the placebo recipients. HCV RNA was undetectable in 79% of TPV recipients and 27% of placebo patients at week 12. Among TPV recipients, 74% and 71% had SVR at weeks 12 and 24, respectively, after treatment cessation compared with 45% and 41%, respectively, of placebo recipients. Two TPV-treated patients experienced HCV RNA breakthrough. No HIV breakthroughs occurred in any patients. CD4 counts remained unchanged throughout treatment. Pruritus, nausea, rash, pyrexia and depression occurred more frequently with TPV use and led to four treatment discontinuations. Dr. Nelson Approximately one-third of HIV-infected patients are coinfected with HCV and are at increased risk for morbidity and liver-related death. Furthermore, treatment of HCV in HIV coinfected patients has traditionally been associated with relatively low SVR rates, limiting enthusiasm to aggressively treat HIV/HCV infected patients. This trial examined the efficacy of TPV, an HCV NS3/4A protease inhibitor associated with notably high SVR rates in HCV monoinfected patients. The SVR rate of 74% with the TPV-based regimen is a remarkable improvement compared with the 45% SVR in the placebo group. Notably, this SVR rate is comparable to response rates observed in HCV monoinfected cohorts. Overall, this TPV-based regimen was well tolerated, and pharmacokinetic analysis showed no alteration in TPV exposure in connection with HIV antiretroviral therapy and no significant impact of TPV on efavirenz or atazanavir exposure. An important point was that the TPV dosing used in this study was increased to 1,125 mg every eight hours, due to the CYP3A enzyme interaction with antiretroviral drugs. The AE profile for TPV in this study cohort was similar to that in HCV monoinfected populations.

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2013

In summary, this study brings new enthusiasm for the treatment of this previously difficult-to-treat population and provides a very solid rationale to consider TPVbased therapy as standard of care for highly selected HIV/HCV coinfected patients.

LB-4.

High Efficacy of GS-7977 in Combination with Low or Full Dose Ribavirin for 24 Weeks in Difficult-to-Treat HCV Infected Genotype 1 Patients: Interim Analysis from the SPARE Trial (Osinusi A et al) This study examined the efficacy of a 24-week IFN-free regimen in 60 difficult-to-treat individuals with HCV infection. Most patients had HCV GT1a, the majority was African American, 80% had the IL28B CT/TT genotype, 48% had a body mass index higher than 30 kg/m2, 23% had advanced liver disease and 62% had HCV viral load greater than 800,000 IU/mL. Sixty-five percent of participants had at least three of these traits, placing them at high-risk for nonresponse to treatment. In the first part of this study, 10 patients with earlystage liver fibrosis received SOF (formerly GS-7977) at a dose of 400 mg/day along with RBV 1,000 to 1,200 mg daily for 24 weeks. In a second part of the study, 50 participants with varying degrees of fibrosis were randomized to receive GS-7977 400 mg daily with RBV 600 mg per day or 1,000 to 1,200 mg per day for 24 weeks.

‘Sofosbuvir, a nucleotide analog that inhibits HCV polymerase, is now being tested in Phase III trials in both IFNcontaining (HCV GT1) and IFN-free (HCV GT2/3) combinations. It will likely gain approval in early 2014 and will offer patients the first all-oral regimen for HCV therapy.’ —David Nelson, MD

Nine of 10 patients in the first part of the study achieved RVR at weeks 4, 12 and 24, and the same number achieved SVR at week 12. The RVR rate in fulldose RBV recipients in the second part of the study was 96% at weeks 4, 12 and 24, and 72% experienced SVR at week 4 after treatment cessation. RVR rates among the low-dose RBV recipients in part 2 of the study were 96% at week 4 and 88% at weeks 12 and 24; low-dose RBV recipients achieved an SVR rate of 56% at week 4. No viral breakthroughs occurred. Paired liver biopsies conducted before and after treatment showed significant relief of hepatic inflammation in all of the patients who experienced a virologic response. There were no serious AEs and no early treatment discontinuations. Dr. Nelson SOF, a nucleotide analog that inhibits HCV polymerase, is now being tested in Phase III trials in both IFNcontaining (HCV GT1) and IFN-free (HCV GT2/3) combinations. It will likely gain approval in early 2014 and will offer patients the first all-oral regimen for HCV therapy. see Best of AASLD, page 23

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GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2013

Lambda continued from page 1

“Improved tolerability, together with faster time to virologic response, supports the further assessment of lambda-based direct-acting antiviral combination regimens in patients chronically infected with HCV genotypes 1 or 4,” said Andrew J. Muir, MD, MHS, clinical director of hepatology at Duke University Medical Center, in Durham, N.C. The study was presented at The Liver Meeting 2012, the annual meeting of the American Association for the Study of Liver Diseases (AASLD; abstract 214). Treatment of HCV infection with peginterferon alfa-2a, a type I interferon (IFN), can be effective, but also causes frequent adverse events, including hematologic toxicity. Lambda is a type III IFN that uses a different signaling pathway and has demonstrated robust antiviral activity. Because it uses a receptor present on fewer types of cells, it has a more favorable tolerability profile than peginterferon alfa. The EMERGE study enrolled 526 noncirrhotic, treatment-naive adults with chronic HCV genotype 1, 2, 3 or 4 infection. Patients were randomized 1:1:1:1 to receive peginterferon alfa 180 mcg, or one of three dosages of Lambda (120, 180 or 240 mcg) administered weekly in combination with daily oral ribavirin. Ribavirin was administered in accordance with the drug label instructions. Patients and providers were blinded throughout the study, and a pharmacist who was unblinded prepared the drug at each study site. The IFN dose could be held and reduced in cases of moderate or severe depression in study subjects or for other significant grade 3 or 4 adverse events (AEs) related to the study drug. Sustained virologic response (SVR) was defined as an HCV RNA level less than the lower limit of quantification (25 IU/mL). At the AASLD meeting, Dr. Muir reported results from the study through week 72 for 407 patients with HCV genotype 1 or 4. “The genotype 1 and 4 patients received 48 weeks of treatment,” he noted. The 240-mcg Lambda dose was reduced to 180 mcg for safety reasons, he said. The average age of study participants was 45 years, and about 50% were men. Dr. Muir said that patients in the 180mcg Lambda treatment arm (n=102) achieved a more rapid virologic response, with similar SVR and relapse rates compared with patients in the peginterferon alfa arm (n=103). Additionally, more patients in the Lambda arm than in the peginterferon alfa arm had undetectable

HCV RNA at various checkpoints during the study, including week 4 (14.7% vs. 5.8%, respectively; P<0.05), week 12 (55.9% vs. 36.9%, respectively; P<0.05), week 48 (57.8% vs. 56.3%, respectively; P=NS) and week 72 (37.3% vs. 36.9%, P respectively; P=NS). P Overall, AEs were similar for both treatments (Table). “From a safety perspective, Lambda had a reduced rate of ribavirin and

Table. Lambda Compared With Peginterferon Alfa Lambda (180 mcg)

Peginterferon Alfa (180 mcg)

Patients with any serious AEs, n

Patients with any AEs, %

88.2

97.1

Patients with interferon dose modifications, %

7.8

28.2

Patients with ribavirin dose modifications, %

10.8

33.0

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2013

peginterferon dose reductions,” said Dr. Muir. “There were fewer musculoskeletal and flu-like symptoms, fewer hematologic abnormalities and similar rates of elevated transaminases and hyperbilirubinemia.” Several AEs of any grade were markedly higher in patients who received Lambda, including myalgia (33% vs. 5.9%), pyrexia (33% vs. 7.8%), chills (21.4% vs. 3.9%) and arthralgia (20.4% vs. 5.9%). All cases

of hyperbilirubinemia resolved following discontinuation of the study drug. Adrian M. Di Bisceglie, MD, chairman, Department of Internal Medicine, Saint Louis University School of Medicine, said that Lambda, with its more forgiving side-effect profile, could have a role in regimens that use IFN, but he noted that a number of IFN-free regimens could potentially come on the market in about two years.

“I think the big question is how many patients will we continue to need interferon for,” Dr. Di Bisceglie said. “These small molecule [IFN-free] combination therapies seem to be very effective in the easier-to-treat patients (genotype 2/3, genotype 1b, those who don’t have cirrhosis, those who are treatment-naive), whereas in patients who are difficult to treat (the previous nonresponders, the cirrhotics, the ones with

‘I think the big question is how many patients will we continue to need interferon for.’ —Adrian M. Di Bisceglie, MD

*Hepatic encephalopathy (HE) recurrence can come crashing in at any time—with catastrophic consequences HE recurrence is a constant, unpredictable threat for most patients. Yet, many go without maintenance therapy for their condition. Prescription claims data from 2011 reveal that 64% of outpatients are not taking any HE medication.1 Even for the minority who are on lactulose, 75% still develop recurrences of HE.2 With each recurrence threatening to leave them disoriented, confused, and less alert at any time, the damage can be devastating.

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References: 1. Data on ﬁle. Salix Pharmaceuticals, Inc, Raleigh, NC. 2. Bajaj JS, Sanyal AJ, Bell D, Gilles H, Heuman DM. Predictors of the recurrence of hepatic encephalopathy in lactulose-treated patients. Aliment Pharmacol Ther. 2010;31(9):1012-1017.

genotype 1a) the response rate is on the low side. We may still need an interferon as part of the treatment regimen for that group of patients, and it is not a trivialsized group,” he said. ■ Dr. Muir has received grant/research support from Abbott Laboratories, Achillion, Bristol-Myers Squibb, GlaxoSmithKline, GlobeImmune, Gilead, Medtronic, Merck & Co., Pfizer, Roche, Salix Pharmaceuticals, Scynexis and Vertex Pharmaceuticals. He serves on advisory committees/review panels for Merck & Co. and Vertex Pharmaceuticals, and he consults for Achillion, Bristol-Myers Squibb, GlaxoSmithKline and Profectus BioSciences. Dr. Di Bisceglie has served on the advisory board and received research support from BristolMyers Squibb, and has served as a scientific advisory board member and received research support/consultancy fees from Abbott Laboratories, Anadys Pharmaceuticals, Bayer, Genentech, Gilead, GlobeImmune, Idenix, Merck & Co., Pharmasset, Salix Pharmaceuticals, Tibotec, Transgene and Vertex Pharmaceuticals.

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

IFN-Free

Sound-C2 Trial

continued from page 1

the section of digestive diseases at the Connecticut Veterans Affairs Healthcare System, West Haven, referring to a future that includes IFN-free regimens for the treatment of HCV infection. “It is going to come to a point where we are going to have a lot of options.” Dr. Garcia-Tsao, who also is president of the AASLD, thinks that some doctors may choose to “warehouse” or delay treating some patients with HCV infection in anticipation of an IFN-free regimen soon becoming available. “It depends on where the patient stands in the natural history of the disease,” she explained. “If you are very early in the fibrotic process, and we think we are going to get more effective oral drugs in the next two or three years, would you wait or would you want to go ahead with current therapies?” It requires a big discussion, she said, and ... doctors need to find out what each patient’s priorities are. Following are highlights from some of the trials of IFN-free therapies presented at the AASLD meeting.

AVIATOR Trial Kris Kowdley, MD, director of research and director of the Liver Center of Excellence at the Digestive Disease Institute, Virginia Mason Medical Center, Seattle, discussed the AVIATOR trial. The trial tested eight-, 12- and 24-week regimens of a combination of ribavirin plus three direct-acting antiviral agents (DAAs) being developed by Abbott Laboratories: ABT-450, ABT-267 and ABT-333. ABT-450, an NS3/4A protease inhibitor, is coadministered with ritonavir (ABT-450/r) in a once-daily dose. ABT-267, an NS5A inhibitor, also is a once-daily therapy. ABT-333, a non-nucleoside polymerase inhibitor, is used twice daily. In exploratory studies, combinations containing ABT-450/r have achieved SVR rates greater than 90% in HCV genotype (GT) 1–infected patients. In the current study, researchers set out to identify the optimal drug combination for HCV GT1–infected patients who were either treatment-naive or null responders to previous treatment with peginterferon and ribavirin. To be eligible, participants could not have cirrhosis or HIV infection. Seven arms of the study, which included 571 patients, were evaluated for different drug combinations and regimen durations, up to 24 weeks. Dr. Kowdley presented results of the eight- and 12-week regimens, which included 448 patients. “Regardless of treatment assignment, very high rates of SVR at week 12 were reached across all categories, both in the treatment-naive and null responders, but in particular, the group receiving three DAAs and ribavirin showed the highest SVR rates,” said Dr. Kowdley, who is clinical professor of medicine at the University of Washington in Seattle. SVR rates at week 12 were 97.5% in the treatment-naive group and 93.3% in null responders. Relapses primarily occurred in patients who received eight weeks of therapy compared with those

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2013

who received 12 weeks. Ninety-six percent of HCV GT1a–infected treatmentnaive patients and 89% of HCV GT1a–infected null responders achieved SVR at week 12. “High SVR12 rates were observed across all interleukin-28B [IL28B] genotypes,” Dr. Kowdley noted. No serious adverse events (AEs) were observed, and only two of the 448 patients discontinued treatment due to an AE attributed to the study drug. “The most commonly reported AEs were fatigue, headache, insomnia and nausea, which were reported infrequently,” Dr. Kowdley said. An 8% rate of fatigue was identified in one group, but all other AEs were observed at rates of 4% or lower. “The only laboratory irregularity that occurred with any frequency was an elevation of total bilirubin, occurring in 6.7% of treatment-naive patients and in 12.2% of null responders.” The researchers said they will be moving the combination of ABT-450/r, ABT-267 and ABT-333 forward in Phase III trials, but ABT-450/r and ABT-267 will be coformulated into one tablet. The regimen will be tested with and without ribavirin.

ELECTRON Trial The ELECTRON trial evaluated sofosbuvir (Gilead Sciences), an NS5B inhibitor, as a backbone of antiviral therapy in patients with HCV GT1-3 infection, for treatment-naive patients and patients who previously had been treated (abstract 229). Various drug combinations have been used in the trial, which has 11 arms so far. Researchers announced that 100% of 25 patients with HCV GT1 infection who were treatment-naive achieved an SVR at week 4 using a combination of sofosbuvir, GS-5885 (Gilead) and ribavirin. HCV genotype or IL28B B genotype did not affect sofosbuvir’s performance. AEs were generally mild: 48% of patients experienced at least two AEs, including anemia (20%), headache (4%) and depression (8%). “In HCV genotype 1 infection, sofosbuvir plus GS-5885 plus ribavirin [taken] for 12 weeks appears to be a safe and effective regimen for treatment-naive patients,” said Edward Gane, MD, deputy director of the New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, who reported the results of the study.

The SOUND-C2 trial tested a combination of two drugs developed by Boehringer Ingelheim, faldaprevir and BI 207127—with or without ribavirin, in treatmentnaive patients with HCV GTI infection (abstract 84). Faldaprevir is a NS3/4A protease inhibitor, and BI207127 is a non-nucleoside NS5B inhibitor. The study, which included 362 patients (33 with cirrhosis), had five arms, testing different dosing schemes and different treatment durations, from 16 to 40 weeks. The 28-week regimen, using a twice-daily dosing scheme performed the best, resulting in a 69% SVR overall at week 12 and an 85% SVR at week 12 in HCV GT1b patients. Patients with cirrhosis achieved an SVR of 67%. The most common AEs were asthenia, pruritus, rash, photosensitivity, jaundice, nausea, vomiting, diarrhea and transient indirect hyperbilirubinemia. Overall, 36% of patients experienced AEs: 12% were considered severe, and 8% led to discontinuation of treatment. The company is launching a Phase III trial to further test this IFN-free drug regimen.

Ribavirin-Free Regimens Mark Sulkowski, MD, medical director of the Viral Hepatitis Center in the Divisions of Infectious Diseases and Gastroenterology & Hepatology at Johns Hopkins School of Medicine, Baltimore, presented results of a study that tested an all-oral combination of daclatasvir (Bristol-Myers Squibb), an NS5A inhibitor, and sofosbuvir, with or without ribavirin (abstract LBA2). The combination—tested in treatment-naive patients—was given for 24 weeks to patients infected with HCV GT1a, GT1b, GT2 or GT3, and for 12 weeks to patients with HCV GT1a or GT1b. All patients were noncirrhotic Researchers randomized 44 patients with HCV GT2/3 to one of three treatment groups: daclatasvir 60 mg daily plus sofosbuvir 400 mg daily with or without ribavirin for 24 weeks, or sofosbuvir daily for seven days and then daclatasvir daily plus sofosbuvir daily for a total treatment time of 24 weeks. Researchers also randomized 44 patients with HCV GT1a/1b to receive sofosbuvir every day for seven days and then daclatasvir and sofosbuvir daily for a total of 24 weeks, or daclatasvir plus sofosbuvir daily, with or without ribavirin, for 24 weeks. During a second stage of the study, 82 patients with HCV GT1a or GT1b were randomized to receive 12 weeks of daclatasvir plus sofosbuvir with or without ribavirin. Overall, more than 93% of patients with HCV GT1, GT2 or GT3 achieved an SVR with the drug combinations. Among the 44 patients with HCV GT2 or GT3 infection, 93% achieved an SVR at week 24, with one patient having a confirmed relapse. Among the 126 patients with HCV GT1 infection, 96% of those who had reached the 12 weeks post-treatment stage had an SVR at week 12; this included three patients who did not have an SVR at week 4. The SVR rate at week 24 in this group was 98%. The drug combination was well tolerated. see IFN-Free, page 22

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IFN-Free continued from page 16

“Virologic response did not vary according to IL28B genotype, viral subtype or with the administration of ribavirin,” Dr. Sulkowski said. “Up until very recently, ribavirin has played a critical role in hepatitis C treatment regimens. It was surprising and also encouraging that this combination—daclatasvir, an NS5A inhibitor, plus sofosbuvir, a nucleotide analog—may not require ribavirin.”

AI443-014 Gregory Everson, MD, director of the section of hepatology at the University of Colorado Denver, in Aurora, presented results from a Phase IIa open-label study of AI443-014 (abstract LBA3), which tested a 12-week regimen of three drugs developed by Bristol-Myer Squibb: daclatasvir, asunaprevir and BMS-791325. The four-armed study included treatment-naive, noncirrhotic patients with HCV GT1 infection. Results were

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presented only for the two arms of the study that included BMS-791325 75 mg plus daclatasvir and asunaprevir. One group of patients was treated for 12 weeks (n=16) and the other was treated for 24 weeks (n=16). Patients (mean age, 48 years) had a high viral load and 75% were infected with HCV GT1a. (The other two study arms received 150 mg of the investigational agent.) In the group receiving treatment for 24 weeks, researchers only had complete data for SVR at week 4 (94%). Two patients assigned to this arm discontinued treatment before completing the 24-week phase: One patient, who withdrew consent at week 9 of treatment, was lost to follow-up (HCV RNA was undetectable at week 8), and the other patient, who stopped treatment at week 14 due to poor venous access, achieved SVR at week 4. In the group that received 12 weeks of treatment, SVR was 94% at weeks 4 and 12. Two patients assigned to this arm discontinued treatment before completing the full 12-week phase: One patient stopped treatment at week 11 but still achieved SVR at week 12, and the other completed the 12 weeks of treatment but failed to return for post-treatment followup (HCV RNA was undetectable at end of treatment). These high rates for SVR were achieved despite the more difficultto-treat characteristics of HCV GT1a infection and non-CC IL28B B genotypes of the patients. Although four patients in the study discontinued treatment prematurely, there were no discontinuations because of AEs. “The regimen was generally well tolerated. There was no viral breakthrough and no post-treatment relapse to date,” Dr. Everson said. “Some of these patients have been followed now for 24 weeks, and with available data to date, we have not yet seen relapse. Further investigation of this regimen in the treatment of hepatitis C is warranted.” The trial is being extended into other populations, including null responders, treatment-experienced patients and patients with more advanced fibrosis. Dr. Everson cautioned, however, that the current results come from a small number of select patients.

Difficult-to-Treat Populations Anu Osinusi, MD, MPH, of SAICFrederick Inc./National Institutes of Health (NIH), Bethesda, Md., presented the interim results of the NIH SPARE (Selective bladder Preservation Against Radical Excision) trial. The two-part trial tested six months of treatment with sofosbuvir in combination with ribavirin in patients with treatmentnaive HCV GT1. In the first phase, 10 patients with stage 0 to 2 fibrosis received sofosbuvir and a weight-based dose of

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2013

ribavirin 1,000 to 1,200 mg per day. In the second phase, 50 patients with all stages of fibrosis, including Child Pugh Class A, were randomized to receive either weightbased or low-dose ribavirin (600 mg) daily. Eighty-three percent of the study population was black, largely overweight, and had the less favorable IL28B CT/TT genotype. A majority of patients had a high HCV viral load and GT1a infection. The investigators found that 77% of patients who received weight-based ribavirin had an SVR at week 4, and 56% of those who received low-dose ribavirin had an at week 4. “There were no safety signals or drugrelated discontinuations in this study,” Dr. Osinusi said.

but highly effective. IFN-free treatment represents a real breakthrough for patients: a high likelihood for SVR; few, if any, side effects; shorter duration of treatment; and newer formulations combining two or more antivirals into a single tablet that will improve compliance to the treatment regimen. Simply speaking, these advances should translate into many more cures.” ■ Drs. Garcia-Tsao and Osinusi reported no conflicts of interest. Dr. Kowdley has received grants/research support from and serves on the advisory board of Abbott

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

Laboratories. Dr. Gane has served on committees and review panels for Boehringer Ingelheim, Gilead Sciences, Jannsen Cilag, Novartis, Pharmasset, Roche and Vertex Pharmaceuticals. Dr. Sulkowski has served as a consultant for Abbott Laboratories, BIPI, Bristol Myers-Squibb, Gilead Sciences, Janssen, Merck & Co., Novartis, Roche/Genentech and Vertex Pharmaceuticals; he has received grants/ research support from Abbott Laboratories, BIPI, Gilead Sciences, Janssen, Merck & Co., Roche/Genentech and Vertex Pharmaceuticals; and he has served on advisory

committees and review panels for Pfizer. Dr. Everson has received grants/research support from Abbott Laboratories, BristolMyers Squibb, Conatus, GlobeImmune, GlaxoSmithKline, Pfizer, Pharmasset, PSC Partners, Roche/Genentech, Schering Plough, Tibotec, Vertex Pharmaceuticals and ZymoGenetics; he has served on advisory committees and review panels for Hep C Connection and Roche/Genentech Merck; he has served as a consultant for Abbott Laboratories and Roche/Genentech; and he has served as a board member for HepQuant LLC and PSC Partners.

Many More Cures “It was not long ago that nearly all hepatologists felt that IFN would always be a mainstay of HCV therapy,” Dr. Everson observed. “The current experience is proving that bias to be wrong: Clearly IFN-free treatment is not only possible

Best of AASLD continued from page 12

This trial evaluated the safety and efficacy of a 24-week regimen of SOF and RBV in treatment-naive patients with HCV GT1 and also looked at the effect of RBV dosing. As has been seen in other SOF-containing regimens, there was rapid viral suppression in all patients, and all failures were due to relapse after therapy was discontinued. Higher rates of relapse were seen in patients with high pretreatment viral load and those with more advanced fibrosis (F3/F4). Week 4 SVR rates of 56% to 72% are encouraging and suggest a beneficial role for higher RBV dosing in this regimen. However, when put into context with other Phase II data suggesting SVR rates of 80% to 100% with more potent all-oral combinations, it is unlikely that this regimen will have significant utility in broad HCV GT1 populations. SOF is potent and has a high barrier to resistance, making it likely to serve as a preferred backbone for future combination therapy with either HCV NS5A-inhibitors or PIs in order to achieve SVR rates above 90%. Although the place of RBV in these regimens is still unclear, this study clearly shows RBV can play a role in relapse prevention. In summary, this study demonstrates the immense promise of IFN-free regimens, but also highlights the continuing need to optimize these regimens. ■ Dr. Nelson has received research grant support from Abbott Laboratories, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead Sciences, Janssen, Merck & Co. and Vertex Pharmaceuticals.

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Indication and Important Safety Information Prepopikâ&#x201E;¢ for oral solution is indicated for cleansing of the colon as a preparation for colonoscopy in adults. r 1SFQPQJL JT DPOUSBJOEJDBUFE JO UIF GPMMPXJOH DPOEJUJPOT QBUJFOUT XJUI TFWFSFMZ SFEVDFE SFOBM GVODUJPO HBTUSPJOUFTUJOBM PCTUSVDUJPO PS JMFVT CPXFM perforation, toxic colitis or toxic megacolon, gastric retention, or in patients with a known allergy to any of the ingredients in Prepopik. Patients should CF BEWJTFE PO UIF JNQPSUBODF PG BEFRVBUF IZESBUJPO BOE QPTU DPMPOPTDPQZ MBC UFTUT TIPVME CF DPOTJEFSFE JG B QBUJFOU EFWFMPQT TJHOJGJDBOU WPNJUJOH or signs of dehydration after taking Prepopik r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r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r 1SFQPQJL TIPVME OPU CF VTFE JG HBTUSPJOUFTUJOBM PCTUSVDUJPO PS QFSGPSBUJPO JT TVTQFDUFE 1SFQPQJL JT OPU GPS EJSFDU JOHFTUJPO &BDI QBDLFU NVTU CF EJTTPMWFE JO PVODFT PG DPME XBUFS BOE BENJOJTUFSFE BU TFQBSBUF UJNFT JO BEEJUJPO UP BEEJUJPOBM DMFBS GMVJET BDDPSEJOH UP UIF EPTJOH SFHJNFO *O SBOEPNJ[FE NVMUJDFOUFS DPOUSPMMFE DMJOJDBM USJBMT OBVTFB IFBEBDIF BOE WPNJUJOH XFSF UIF NPTU DPNNPO USFBUNFOU FNFSHFOU BEWFSTF SFBDUJPOT (>1%) following Prepopik administration 1MFBTF TFF CSJFG TVNNBSZ PG 1SFTDSJCJOH *OGPSNBUJPO GPMMPXJOH UIJT BEWFSUJTFNFOU

New Prepopik helps patients arrive ready with: t Lowest volume of active prep solution and a flexible hydration schedule1 t Demonstrated non-inferiority, with both split-dose and day-before regimen1 t S uperior cleansing efficacy with ACG-recommended split-dose vs day-before regimen comparator*1 – 84% vs 74%, respectively, achieving “excellent or good” visualization, validated per the Aronchick scale* t A dual mechanism that stimulates peristalsis and produces osmotic water retention1 *Evaluated in a randomized trial. The comparator was 2L PEG with electrolytes (PEG+E) plus 2x 5 mg bisacodyl tablets, dosed as labeled. The primary efficacy endpoint was the proportion of patients with successful colon cleansing defined as bowel preparations with >90% of the mucosa seen and mostly liquid stool, assessed by blinded colonoscopists.1

To learn more, scan this code with your smartphone, or go to www.prepopik.com.

Reference: 1. Prepopik™ Prescribing Information, July 2012. Ferring Pharmaceuticals Inc. Parsippany, NJ 07054, USA.

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

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

PEG-IFN Add-On Therapy May Improve Response To Entecavir in Patients With Hepatitis B BY KATE Oâ&#x20AC;&#x2122;ROURKE BOSTONâ&#x20AC;&#x201D;Adding peginterferon alfa2a (PEG-IFN) to entecavir (Baraclude, Bristol-Myers Squibb) increases treatment response in patients with chronic hepatitis B virus (HBV) infection who are hepatitis B e-antigen (HBeAg)-positive,

according to preliminary results from an international clinical trial. Presented at The Liver Meeting 2012 (abstract 19), the results suggest a strategy for helping this patient population avoid the need for indefinite therapy. â&#x20AC;&#x153;Adding PEG-IFN alfa-2a to entecavir increases HBV DNA, HBeAg and HBsAg [hepatitis B surface antigen] Aspiration 3DWLHQWV ZLWK LPSDLUHG JDJ UHĂ&#x20AC;H[ DQG SDWLHQWV SURQH WR UHJXUJLWDWLRQ RU DVSLUDWLRQ VKRXOG EH REVHUYHG GXULQJ WKH DGPLQLVWUDWLRQ RI PREPOPIK. Use with caution in these patients.

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decline,â&#x20AC;? said Milan Sonneveld, MSc, of Erasmus University Medical Center, Rotterdam, Netherlands, who presented the study at The Liver Meeting. Entecavir is a potent inhibitor of HBV replication in HBeAg-positive patients with chronic HBV infection. Because discontinuation of this nucleoside analog after HBeAg seroconversion results in

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â&#x20AC;&#x2DC;The most important point is that adding PEG-IFN alfa-2a to a potent nucleoside analog appears to increase the probability of finite treatment in HBeAg-positive chronic hepatitis B patients.â&#x20AC;&#x2122; â&#x20AC;&#x201D;Milan Sonneveld, MSc

relapse in the majority of patients, current treatment guidelines recommend continuing therapy until HBsAg loss is achieved. â&#x20AC;&#x153;Long-term entecavir treatment results in only a limited surface antigen decline, and the estimated duration of treatment required before surface antigen loss is therefore expected to be at least three decades,â&#x20AC;? said Mr. Sonneveld, explaining the logic behind the study. â&#x20AC;&#x153;PEGIFN treatment, however, results in more of a decline and clearance of e-antigen and of surface antigen than does entecavir [alone], and serologic response to PEG-IFN is highly durable, even after discontinuation of treatment. Temporary addition of PEG-IFN to entecavir therapy therefore may increase the probability of serologic response.â&#x20AC;? In the study, 184 HBeAg-positive patients with compensated liver disease were selected and randomized to receive entecavir 0.5 mg daily for 48 weeks, with or without a 24-week addition of PEG-IFN alfa-2a 180 mcg initiated at week 24. Patient response was assessed at week 48, and responders were allowed to discontinue treatment after 24 weeks of consolidation treatment (week 72), with subsequent follow-up until week 96. Patients were enrolled at 15 sites across Europe and China.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2013

‘The preliminary results of this study have shown that the addition of PEG-IFN after six months of entecavir resulted in higher rates of HBV decline, HBeAg loss and decline in HBsAg levels, than entecavir monotherapy.’ —Mandana Khalili, MD

irrespective of the baseline surface antigen level.” Add-on PEG-IFN was well-tolerated and safe. The most serious adverse event was grade 4 neutropenia, which was seen in two patients. “The most important point is that adding PEG-IFN alfa-2a to a potent nucleoside analog appears to increase the probability of finite treatment in HBeAg-positive chronic hepatitis B patients,” said Mr. Sonneveld. Mandana Khalili, MD, professor of medicine and chief of clinical

hepatology, San Francisco General Hospital, University of California, said that strategies to improve seroconversion, maintain treatment response and increase rates of optimal end points of therapy, specifically HBsAg seroconversion, are of clinical importance to the management of HBV. “The preliminary results of this study have shown that the addition of PEGIFN after six months of entecavir resulted in higher rates of HBV decline, HBeAg loss and decline in HBsAg levels, than entecavir monotherapy,” Dr. Khalili said.

“This study highlights a potential for benefit of combination therapy for HBV, but it is still too early to make firm recommendations or to change current standard of care practice. It is also important to understand the sustainability of the virologic responses with such strategies, which would be the key for their applicability in the future.” ■ Dr. Sonneveld has received speaker’s fees from Roche. Dr. Khalili has received grants from Bristol-Myers Squibb and Gilead, and is a member of Gilead’s advisory board.

The latest innovation in Endoscopy Self-Assessment Mr. Sonneveld presented 48-week results for 83 patients who received entecavir alone and for 77 patients who received combination therapy. A greater percentage of patients who received addon therapy achieved HBV DNA level of less than 200 IU/mL (83% vs. 74%) and HBV DNA level of less than 20 IU/ mL, but the differences were not statistically significant (P=0.523 P and P=0.340, P respectively). Additionally, a greater number of patients in the add-on group achieved HBeAg loss (18% vs. 8%) and HBeAg loss plus HBV DNA less than 200 IU/mL (18% vs. 8%), but those differences just missed statistical significance (P=0.068 P for both). “In a multivariate analysis, only lower levels of surface antigen and adding peginterferon were independent predictors of achieving a response at week 48,” Mr. Sonneveld said. The probability of response in an absolute sense decreased with increasing levels of surface antigen at baseline, Mr. Sonneveld said. “This means that if a patient has a higher level of surface antigen before he starts treatment, the probability of achieving a response in e-antigen loss goes down. However, adding PEG-IFN increases the probability of response,

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References: 1. Jensen RT, Doherty GM. Carcinoid tumors and the carcinoid syndrome. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:1559-1574. 2. Caplin ME, Buscombe JR, Hilson AJ, Jones AL, Watkinson AF, Burroughs AK. Carcinoid tumour. Lancet. 1998;352(9130):799-805.

What’s behind the symptoms? Carcinoid Syndrome Can Be Deceptive Early diagnosis of carcinoid syndrome is essential. The most common symptoms of carcinoid syndrome are severe diarrhea, ﬂushing, abdominal pain, cardiac disease, wheezing, and telangiectasia.1,2 To learn more, visit www.carcinoidfacts.com.

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Hepatic Encephalopathy Explored in New Film, Studies HE is associated with tremendous costs for sufferers, their caregivers and health care systems. One study showed that among patients with cirrhosis, 87.5% who had a previous HE episode experienced unemployment and posed a higher caregiver burden compared with those who had not experienced an HE episode (Bajaj JS et al. Am J Gastroenterol 2011;106:1646-1653). Other studies have shown that hospitalizations due to HE have more than doubled in the past decade, and costs associated with hospitalizations rose from $13,000 in 1993 to $30,000 per hospital stay in 2007 (Neff G. Pharmacotherapyy 2010;30:28S-32S).

BY CHRISTINA FRANGOU

Undertreatment a Problem

The film was ‘created to capture the stories of patients who often do not have the comprehensive support they desperately need.’ —Cynthia Wade, director, “Wrestling the Monster”

Jamile Wakim-Fleming, MD, a gastroenterologist at the Cleveland Clinic with a special interest in liver disease, said the documentary can help educate families and primary care physicians about HE. Interestingly, she noted that the patients in the documentary were more lucid than many patients experiencing an acute episode. “We need family, neighbors and primary care physicians to learn the early signs and watch for them. That’s most important,” Dr. Wakim-Fleming said. “As a liver specialist, I’m not going to see those little

changes that happen outside the office. But if we can detect it early with the family’s help, you can prevent overt hepatic encephalopathy and all the consequences.”

Increasing Prevalence Becoming a Burden HE is on the rise, an echo of the increasing prevalence of chronic liver disease in the United States. Estimates suggest that approximately 600,000 people in the United States develop cirrhosis, and all patients with cirrhosis are at risk for HE.

Many patients do not receive ongoing treatment as outpatients following an episode of HE, according to a study presented at The Liver Meeting 2012 (poster 1612). An analysis of national claim data showed that nearly two-thirds of patients seen by physicians after an episode of overt hepatitis remained untreated as outpatients. Of eligible patients in 2011, 63.9% did not receive ongoing treatment. Similar rates were reported in 2009 at 60.3% and 2010 at 62.3%. The finding was based on national claims for medical and hospital activity collected by Source Healthcare Analytics. The investigators could not discern why treatment rates remain low but suggested some plausible causes: patients failing to fill prescriptions due to lack of insurance; other financial concerns and/or noncompliance; and/or health care providers not being see Hepatic Encephalopathy, page 32

All photos in this story are stills from the film “Wrestling the Monster: Living With Hepatic Encephalopathy.”

A new documentary and several new studies are bringing attention to an often overlooked and undertreated form of liver disease: hepatic encephalopathy (HE). The documentary, a 30-minute film called “Wrestling the Monster,” follows four patients and their caregivers as they struggle with the effects of HE, a deterioration of brain function that occurs when the liver is no longer able to remove toxic substances from the blood. The film, which is accessible online at www.hesback.com, is co-sponsored by the American Liver Foundation and Salix Pharmaceuticals; Salix markets Xifaxan (rifaximin) for reduction in risk for overt HE recurrence in patients aged 18 years or older. The film does not advertise a specific treatment; instead, it focuses on portraying the tremendous psychological and physical effects of HE. Several scenes in the movie depict quite graphically the distress experienced by patients with HE and their families. In one scene, a young boy and his mother survey the ruins of the family’s living room after his father rips it apart in a rage; in another, Lynette, a well-spoken former office manager, falls into a stupor midsentence and gapes at the camera for four minutes while tears fall down her face. Director Cynthia Wade—who won an Academy Award for her 2007 documentary “Freeheld”—said the film was “created to capture the stories of patients who often do not have the comprehensive support they desperately need.”

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Hepatic Encephalopathy continued from page 30

percentage of patients have been treated with rifaximin annually. In 2009, 3.9% of patients received rifaximin alone, 8.1% received rifaximin and lactulose and 27.9% received lactulose alone, compared with 13.2%, 8.8% and 14.1%, respectively, in 2011.

New Data Support HE Treatment Several updates on trials involving rifaximin for the treatment of HE were presented at The Liver Meeting, including:

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Poster 1548. A double-blind trial of 299 patients randomized to receive rifaximin (n=140) or placebo (n=159) showed that rifaximin protected against overt HE as evaluated by Conn score and significantly improved Critical Flicker Frequency (CFF) performance versus placebo. The CFF test independently predicted breakthrough HE and a cutoff of 32 Hz was predictive of overt HE. The findings establish CFF as a viable alternative or adjunct to Conn score for the grading of HE in a large multicenter six-month trial of patients with cirrhosis. Posters 1545, 1573. In two studies of 16 patients with minimal HE who underwent functional magnetic resonance imaging before and after receiving rifaximin 550 mg twice daily for eight weeks, researchers identified some of the changes in the brain that occur with rifaximin treatment and contribute to improved cognition. Both studies showed increased fronto-parietal activation in patients taking rifaximin, leading to improved cognition, reduced white matter cytotoxic brain edema and enhanced working memory in minimal HE. These are the first data to show the functional basis for cognitive improvement in minimal HE with rifaximin.

Poster 1567. In a crossover analysis of patients initially enrolled in a doubleblind trial comparing rifaximin with placebo, 82 patients who had more than two HE episodes in the past were switched from placebo to rifaximin and experienced a similar protective effect against breakthrough HE episodes compared with patients who received rifaximin originally. Investigators concluded, “this provides evidence that introduction of [rifaximin] therapy is important for preventing HE recurrence, and its clinical sequelae.” ■ Dr. Wakim-Fleming reported no conflicts of interest. Dr. Neff has received grants and/ or research support from Salix Pharmaceuticals; he serves as a consultant for Gilead, Salix and Vertex Pharmaceuticals; and he is a speaker for Bristol-Myers Squibb, Genentech, Merck & Co. and Salix. Posters 1548 (Butterworth et al. A critical flicker frequency value of 32 Hz predicts recurrence of overt hepatic encephalopathy in a double-blind, placebo controlled trial of rifaximin in patients with cirrhosis) and 1567 (Bajaj et al. Long-term use of rifaximin is associated with reduced hospitalizations, prolonged remission: a placebo crossover analysis) were funded by Salix Pharmaceuticals.

All photos in this story are stills from the film “Wrestling the Monster: Living With Hepatic Encephalopathy.”

adequately educated about the benefits of treatment. They concluded that correcting the “apparent undertreatment of HE in an effort to reduce recurrences and hospitalizations, enhance quality of life and potentially reduce long-term cognitive deficits, will be primary challenges in the future.” “Patients with cirrhosis and their caregivers should all be aware of the signs and symptoms of HE,” said Guy Neff, MD, chief of hepatology for Tampa General Medical Group, in a press statement. Both Drs. Neff and Wakim-Fleming emphasized the need for treatment. “HE will not get better without treatment,” said Dr. Neff. “However, once diagnosed, overt recurrences of HE can be managed and even prevented with the right medication.” Several lines of treatment are available, including dietary therapy and drug treatment with lactulose and rifaximin. The aforementioned study showed that, although the percentage of patients receiving treatment has remained stable, the treatment paradigm is shifting. Following the FDA’s March 2010 approval of rifaximin for reduction in risk for overt HE recurrence in adults, an increasing

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3 33 3

Real-World continued from page 1

This news comes from two studies presented at The Liver Meeting, the annual meeting of the American Association for the Study of Liver Diseases. Researchers say that treatment rates are low because of the complexity of treatment with the direct-acting antivirals (DAA) and concerns about side effects, even at experienced centers. The FDA approved boceprevir and telaprevir for the treatment of patients with hepatitis C virus (HCV) genotype 1 infection in combination with pegylated interferon and ribavirin in 2011. Fasiha Kanwal, MD, MSHS, associate professor at Baylor College of Medicine, in Houston, who was not involved with the study, said she was not surprised by the high discontinuation rates of these two agents. “With the addition of the new DAAs, the probability of cure is much higher (approximately 70% in clinical trials) and the duration of treatment may be half as long for some patients, but the side effect burden is significantly greater than the previous standard,” Dr. Kanwal said. “Moreover, participants in the DAA registration trials were generally much healthier than most HCV patients in routine practice, who often have physical or mental comorbidities that may complicate treatment. The fact that rates of treatment-related adverse events and resulting discontinuations are higher in these community-based patients is therefore not surprising.”

High Discontinuation Rates In one of the studies presented at The Liver Meeting, researchers reviewed the medical charts of all adult HCV patients being treated with DAA triple regimens over a one-year period at the University of Texas Southwestern Medical Center, in Dallas, and a referral center at the University of Miami Health System, in Florida (abstract 133). All patients had at least 12 weeks of follow-up. Researchers excluded patients who were post-transplant, receiving dialysis or coinfected with HIV. Of the 454 patients at the two centers, only 19% began triple therapy. Reasons for treatment deferral included early disease stage (19%), comorbidities (18%) and advanced liver disease (13%). The overall discontinuation rate of the triple therapy was 21% before week 12. This discontinuation rate was higher than that seen in the trials that led to the telaprevir approval, with the ADVANCE trial showing a 10% discontinuation rate and REALIZE showing a 13% discontinuation rate ( Jacobson IM et al. N Engl J Medd 2011;364:24052416; Zeuzem S et al. N Engl J Med

‘Participants in the DAA registration trials were generally much healthier than most HCV patients in routine practice, who often have physical or mental comorbidities that may complicate treatment. The fact that rates of treatment-related adverse events and resulting discontinuations are higher in these community-based patients is therefore not surprising.’ —Fasiha Kanwal, MD, MSHS

2011;364:2417-2428). This rate is also higher than the rates seen in the trials that led to boceprevir’s approval, which was roughly 2% in the Sprint-2 trial and 8% and 12% in the two boceprevir arms in the RESPOND-2 trial (Poordad F et al. N Engl J Medd 2011;364:11951206; Bacon BR et al. N Engl J Med 2011;364:1207-1217). In a second study, researchers reviewed see Real-World, page 35

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2013

FDA Adds Boxed Warning for Serious Skin Reactions to Telaprevir

Serious skin reactions, some fatal, have been reported with the use of telaprevir (Incivek, Vertex Pharmaceuticals), a hepatitis C virus (HCV) protease inhibitor, used in combination with peginterferon alfa and ribavirin, according to an FDA drug safety communication issued on Dec. 19. Some patients died when they continued to receive the combination therapy after developing a progressive skin rash and systemic symptoms. In light of these reports, the FDA has added a boxed warning to the drug label for telaprevir, stating: “If serious skin reactions occur, all three components of Incivek combination treatment, including peginterferon alfa and ribavirin, must be immediately discontinued, and the patient should receive urgent medical care.” Discontinuation of other medications known to be associated with serious skin reactions also should be considered, the FDA recommended. Nancy S. Reau, MD, a hepatologist and associate professor of medicine at the University of Chicago, noted that skin reactions associated with telaprevir were described at the time the drug was approved in 2011.

identified 92 cases of drug rash with eosinophilia and systemic symptoms (DRESS) and 20 cases of Stevens-Johnson syndrome (SJS) in patients who received telaprevir combination treatment. One of these cases was fatal, a 47-year-old woman who continued taking telaprevir combination therapy after DRESS developed. The fatal case of TEN from Japan occurred in a 69-year-old man who continued to receive telaprevir combination treatment for a period of time after skin symptoms developed. Dr. Reau noted that the recommendation by the FDA to discontinue all three components of telaprevir combination treatment, including peginterferon alfa and ribavirin, in patients with serious skin reactions is new. “If there’s SJS, we discontinue all components of the combination therapy,” Dr. Reau said. In contrast, “if it’s severe rash, many of us are inclined to stop the telaprevir but continue the interferon and ribavirin.” In the treatment of her own patients, Dr. Reau said, “I don’t always discontinue all therapy for severe rash. If there is severe rash over more than 60% of the body but no mucosal involvement, especially if it is close to the 12-week end of telaprevir therapy, I wouldn’t discontinue peginterferon and ribavirin. But Photo courtesy of Vertex Pharmaceuticals

BY GEORGE OCHOA

“This is a reminder to assess our patients,” Dr. Reau said of the current FDA warning. “Discontinue all therapy for people who are toxic. Patients complaining of rash should be closely monitored.” They should be seen in one or two weeks—not in a month—and continue to be monitored. “Nothing can trump actually seeing the patient,” she said. Notable in the FDA’s most recent safety communication is the addition of two reports from Japan, of patients with toxic epidermal necrolysis (TEN). In one of these patients, TEN was fatal. A search of the FDA Adverse Event Reporting System database from May 23, 2011 to June 19, 2012,

see Telaprevir, page 35

Montefiore Einstein Center for Transplantation

A World-Class Center of Excellence Dedicated to Liver Disease multidisciplinary integrated practice bringing experts together in hepatology, advanced hepatobiliary surgery and liver cancer. One-Year Adult Patient Survival Rate The Marion Bessin Liver Research Center at Albert Einstein College of Medicine is one of the oldest continuously funded National Institutes of Health Liver Centers in the United States and has 40 faculty investigators. More than 200 adult and pediatric patients have been evaluated in Montefiore’s new liver transplant program.

90%

93%

Montefiore 89%

U.S. National Average

The Children’s Hospital at Montefiore has a dedicated hepatology and transplant program and is ranked among America’s top pediatric hospitals by U.S. News & World Report.

80%

To refer or discuss an outpatient, please call 888-RX-LIVER (888-795-4837) or 718-920-2800 for inpatient transfers.

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To watch our vignette on stem cell research or to learn more about the Montefiore Einstein Center for Transplantation, visit www.montefiore.org/transplant

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2013

Real-World continued from page 33

the records of HCV patients treated with telaprevir-based triple therapy at Mount Sinai Medical Center and Montefiore Medical Center, both in New York City (abstract 1755). Patients had at least 12 weeks of follow-up. Of 157 patients who initiated the triple therapy, 32% discontinued telaprevir prematurely and 21% discontinued treatment due to adverse events. Discontinuation rates were similar in patients with stage F0-F2 and F3-F4 fibrosis. Discontinuation due to adverse events was almost 10% greater than the REALIZE trial that led to telaprevir’s approval (21% vs. 13%; P=0.01). P Dr. Kanwal said that DAAs are effective, and treatment response in clinical practice has been approximately twice as high as seen with pegylated interferon and ribavirin alone. “Given this, I believe that the message for the clinicians is that these new agents [boceprevir and telaprevir] hold promise, particularly for patients with more advanced fibrosis or cirrhosis, where watchful waiting may not be appropriate. For patients with less advanced fibrosis, waiting for other ‘in-the-pipeline’ antivirals may be a reasonable alternative,” Dr. Kanwal said.

“Treatment decisions in this new era of DAAs may need to be informed with not only the scientific knowledge base of the treating clinician, but also patients’ perceptions of outcome expectancies, risks and benefits associated with the available options and subsequent preferences for treatment,” she added.

Drug–Drug Interactions Overlooked In another study (abstract 136), researchers found that in the real world, HCV patients frequently use drugs

that have the potential to interact with boceprevir and telaprevir. This study was presented at The Liver Meeting by Christina Mayer, PharmD, a postdoctoral research associate at the University of North Carolina at Chapel Hill’s Eshelman School of Pharmacy. Investigators identified adults with chronic HCV infection in a large commercial claims database; drugs with the potential to interact with boceprevir or telaprevir were identified using www.hep-druginteractions.org. Of the 20 most frequently filled prescriptions by 71,584 patients, six

Brief Summary Please consult Package Insert for full prescribing information.

had potential for a drug–drug interaction and four had clear indications. For example, 17% of patients were using zolpidem, 14.3% were using tramadol and 11.8% were using alprazolam, all of which have interactions with both boceprevir and telaprevir. Other frequently used drugs that interact with these two DAAs included amlodipine (10.2%), escitalopram (8.1%) and bupropion (7.2%). ■ Drs. Kanwal and Mayer reported no relevant conflicts of interest.

the properties of the gel and may cause device malfunction.

Indication for Use Solesta is indicated for the treatment of fecal incontinence in patients 18 years and older who have failed conservative therapy (eg, diet, ﬁber therapy, antimotility medications). Contraindications Solesta is contraindicated in patients with the following conditions:

may damage or alter the product.

damage or alter the product. other infections should be in accordance with accepted medical practice and applicable local, state and federal requirements.

Telaprevir

Warnings

continued from page 34

vascular occlusion.

for anything more systemic, I would stop all treatment, especially because new drugs are in development that may provide an alternative.” Regarding the FDA’s advice to consider stopping other medications that might be associated with serious skin reactions, Dr. Reau said that this is a difficult statement to interpret. “Ribavirin is part of the backbone of HCV therapy and has a rash signal, but this drug is also vital for treatment efficacy. Infections are also common during HCV therapy and antibiotics can cause rash. I would have hoped for more guidance.” Dr. Reau noted that the risk for serious skin reaction with telaprevir combination therapy is “pretty small.” She stated, “The black box warning could deter patients and prescribers. But a person with a risk–benefit profile in favor of therapy should be considered for treatment despite this change.” ■

enlarged prostate.

Potential adverse events include: abdominal discomfort, abdominal distension, abdominal pain, lower abdominal pain, abdominal rigidity, alopecia, anal abscess, anal ﬁssure, anal hemorrhage, anal prolapse, anal pruritus, anorectal discomfort, back fecal incontinence, feces hard, fatigue, gastrointestinal motility disorder, gastrointestinal

Dr. Reau has conducted research for Vertex Pharmaceuticals and has served as a consultant for Abbott Laboratories, Bristol-Myers Squibb, Genentech, Gilead, Janssen, Kadmon and Vertex.

Precautions General pprecautions procedures and who have successfully completed a comprehensive training and

abscess, nausea, edema, pain, painful defecation, pelvic mass, perineal pain, proctalgia, rectal obstruction, rectal prolapse, rectal spasm, rectal tenesmus, rectovaginal septum

previous procedures involving the anorectal region: rectal anastomosis <12 cm from anal verge, anorectal surgery within previous 12 months, hemorrhoid treatment with

studies.

age of 18 years. breastfeeding women. Directions for Use of anorectal conditions and who have successfully completed a comprehensive training treatments, four weeks apart. Patient related precautions p

disorders. Please consult Package Insert for full directions for use and method of administration. How Supplied

required to achieve a satisfactory level of improvement in incontinence. Procedure related precautions p

Storage recommended. which could cause leakage of the gel. *Safety information presented in the Package Insert only includes data up to 18 months.

A significant achievement for patients with fecal incontinence (FI)...

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Itâ&#x20AC;&#x2122;s no accident. Solesta: a unique treatment for FI t An injectable, biocompatible gel t Nonsurgical, in-office procedure t No anesthesia required t May preclude need for more invasive surgical procedures

Durable efficacy with Solesta

Solesta is indicated for the treatment of fecal incontinence in patients 18 years and older who have failed conservative therapy (eg, diet, fiber therapy, anti-motility medications). The most common adverse reactions (incidence >2%) are proctalgia, anorectal hemorrhage, injection site hemorrhage, pyrexia, injection site pain, diarrhea, and anorectal discomfort.

Number of episodes/14 days

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Solesta should be administered by qualified physicians with experience in the treatment of anorectal conditions.

Please see brief summary of full Prescribing Information on following page.

P=0.001

n=136

20 15 10

15.0

53%

8.6

6.2

7.0

0 Baseline

Months