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Digestive Disease Week 2016
This year’s Digestive Disease Week, held May 21–24 in San Diego, California, hosted more than 14,000 attendees. Below we review key sessions on hepatitis C, Clostridium difficile, colonoscopy preparation, irritable bowel syndrome with diarrhea, and Crohn’s disease.
Comparative Effectiveness of Ledipasvir/Sofosbuvir ± Ribavirin and Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir ± Ribavirin In 6,961 Genotype 1 Patients Treated in Routine Medical Practice
In 2014, the Food and Drug Administration approved ledipasvir/sofosbuvir (LDV/SOF) with or without ribavirin (RBV) and ombitasvir/paritaprevir/ritonavir plus dasabuvir (OPrD) with or without RBV for the treatment of hepatitis C virus (HCV) infection. Veterans Affairs, the largest integrated provider of HCV care, conducted an intent-to-treat cohort analysis of patients receiving a first course (eight to 12 weeks) of LDV/SOF with or without RBV or OPrD-based therapy in its 126 facilities.
While the sustained virological response (SVR) rates in clinical trials among genotype 1 HCV patients (the most prevalent group) were more than 90%, differences between outcomes in clinical trials versus those in routine medical practice have been observed often with prior HCV regimens. This study’s goal was to assess the effectiveness of these newer, more expensive pharmacotherapies in routine medical practice. The trial’s primary endpoint was SVR (HCV RNA below the limit of quantification after the end of treatment).
SVR rates (85.8% for OPrD with or without RBV; 95.1% with OPrD [1b]) with LDV/SOF with or without RBV or OPrD with or without RBV in routine medical practice nearly matched the high rates seen in clinical trials, Dr. Backus said. SVR rates were uniformly higher (except in human immunodeficiency virus patients) across subgroups in patients who received 12 weeks of treatment versus eight weeks of treatment. SVR rates were lower in patients 55 to 64 years of age; in African-Americans (odds ratio [OR], 0.71 [0.59–0.86]; P < 0.01); in those with a body mass index of 30 kg/m2 or higher (OR, 0.73 [0.60–0.89]; P < 0.01); in those with liver disease-severity marker Fibrosis–4 scores over 3.25 (OR, 0.60 [0.49–0.72]; P < 0.001); and in those receiving OPrD with RBV (OR, 0.60 [0.48–0.76]; P < 0.001).
Among 6,961 HCV patients, early discontinuations were lowest for LDV/SOF (5.35%) and highest for OPrD with RBV (15.2%), with rates somewhat higher among African-Americans. Dr. Backus noted also that LDV/SOF has a lower pill burden and frequency than the OPrD regimen.
Systematic Review and Meta-Analysis of Probiotics for Preventing Clostridium Difficile Infection in Hospitalized Adults Taking Antibiotics
Clostridium difficile infection (CDI) is the leading health care-associated infection in hospitalized adults taking antibiotics in the U.S., according to Dr. Shen. Prior meta-analysis–based reviews suggest that CDI may be prevented by concurrent probiotic/antibiotic use. Probiotics are not recommended in the current American College of Gastroenterology and Society for Healthcare Epidemiology of America guidelines, although a 2015 Modified Delphi panel unanimously recommended CDI prophylactic use of Lactobacillus acidophilus and L. casei concurrently with antibiotics.
To determine if probiotics prevent CDI in hospitalized adults receiving antibiotics, Dr. Shen and colleagues conducted a meta-analysis including 6,942 patients (3,665 taking probiotics versus 3,277 controls) in 19 studies. Among individuals excluded from the analysis were those with diarrhea, compromised immunity, and acquired immune deficiency syndrome; those receiving chemotherapy or radiation; those with a history of CDI within three months; and those with gastrointestinal disease, inflammatory bowel disease, pancreatitis, ostomy, or artificial heart valves.
Dr. Shen’s analysis found a CDI rate of 1.5% among those taking concurrent probiotics and a rate of 3.5% among controls. The number needed to treat was 50. Of the 19 trials, 17 showed a benefit for probiotics. The analysis also showed that probiotic efficacy was higher in those studies showing higher CDI incidence. Adverse events were similar between groups (probiotic relative risk, 0.97 [0.86–1.09]).
Probiotic species, formulation, and dose did not affect efficacy. Dr. Shen pointed out that timing of probiotic use after the first antibiotic dose was the one consequential factor. The CDI relative risk was 0.32 among those taking the probiotic less than two days from the first antibiotic dose (P < 0.001), and it was 0.70 among those taking it more than two days from the first antibiotic dose (P = 0.02).
Overall, the quality of evidence was high, and Dr. Shen concluded that probiotics safely and effectively reduce CDI risk by more than 50% in hospitalized patients taking antibiotics. Further studies are needed to identify optimal species, dose, and duration.
“The findings suggest that as soon as you start taking antibiotics, you may be altering the gut flora in a way that creates vulnerability to CDI,” Dr. Shen said. The findings are strong enough, she said, to justify a guidelines change for those patients not among groups excluded from the analysis.
Single-Day Low-Residue Diet Prior to Colonoscopy Shows Improved Tolerance and Bowel Preparation Quality Over Clear Liquid Diet: Interim Results From a U.S. Multicenter Randomized Controlled Trial
Despite the fact that colonoscopy has been shown to reduce colon cancer deaths, screening participation remains low, Dr. Samarasena said. A factor often cited by patients as a strong deterrent is the dietary restriction associated with bowel preparation. “The clear-liquid diet [CLD] allowing only ‘Jell-O’ and drinks or broth you can see through leaves some people tired and hungry and is seen as uncomfortable and a hassle,” he said. Some practitioners have adopted a low-residue diet (LRD) allowing solid food that liquefies quickly in the small intestine. This low-fiber diet excludes vegetables, fruits, and seeds, but permits foods such as scrambled eggs, ice cream, macaroni and cheese, and even chicken breasts; it provides more calories and nourishment. Large studies comparing LRDs and CLDs are few, however.
The aim of this multicenter, randomized, single-blind prospective trial was to compare an LRD to a CLD in regard to bowel preparation quality, along with tolerance and satisfaction among a diverse patient population. It was conducted at a tertiary geriatric care center and a Veterans Administration hospital and included 83 patients undergoing colonoscopy. Investigators evaluated bowel preparation adequacy with the 10-point Boston Bowel Preparation Scale (BBPS) and hunger and fatigue pre- and postprocedure with a 10-point scale. They also assessed nausea, vomiting, bloating, abdominal cramping, and overall discomfort, as well as satisfaction with the diet, willingness to repeat the same preparation (diet and purgative), and the overall experience.
Interim analysis showed the BBPS for the LRD group to be better at 7.98 out of 10, compared with 7.54 out of 10 for the CLD group, with bowel preparation assessed as “adequate” in a higher number of patients in the LRD group (P = 0.05). BBPS scores of 7, 8, or 9 with no segment score of 0 or 1 were considered adequate.
As expected, evening hunger scores just prior to purgative intake were significantly lower in the LRD than the CLD group (3.5 versus 6.9, respectively; P = 0.001), and morning post-prep fatigue scores were also significantly lower in the LRD than the CLD group (3.5 versus 6, respectively; P = 0.01). Symptom scores were similar between groups, and diet satisfaction was higher in the LRD group (97% versus 46%; P < 0.001).
“This interim analysis demonstrates that patients using a low-residue diet before colonoscopy achieve a bowel preparation quality that may be superior to patients on a clear-liquid diet restriction. It shows also that a low-residue diet improves patient satisfaction and results in significantly better tolerability of bowel preparation. As a less restrictive dietary regimen, low-residue diet may help improve patient participation in colorectal cancer screening programs,” Dr. Samarasena said.
Lack of Abuse Potential of Eluxadoline: Data From Phase 2 and 3 Studies
Eluxadoline, an oral mixed mu-opioid receptor (OR), kappa-OR agonist, and delta-OR antagonist with low oral bioavailability (2–4 ng/mL), is approved by the Food and Drug Administration (FDA) for the treatment of adults with irritable bowel syndrome with diarrhea (IBS-D). With eluxadoline’s site of action occurring at the opioid receptors, its potential to be abused and to cause withdrawal symptoms is of interest and was evaluated at therapeutic doses (75 or 100 mg) in three phase 2 and phase 3 clinical trials (phase 3, IBS-3001 and IBS-3002; phase 2, IBS-3001). These trials have shown that eluxadoline (compared with placebo) improves abdominal pain and stool consistency in IBS-D patients and is well tolerated.
The trials included 2,776 patients (mean age, approximately 45 years; approximately 67% female; approximately 86% white). Analysis showed the overall incidence of adverse events potentially related to abuse to be similar across groups at 2.8% for placebo, 2.7% for eluxadoline 75 mg, and 4.3% for eluxadoline 100 mg. The assessment was based on the analysis of 210 terms proposed by the FDA in 2013 to capture abuse-related adverse events.
The most common adverse events potentially related to abuse were anxiety and somnolence, both of which occurred in less than 2% of patients in each treatment group. In the two-week post-treatment period (IBS-3001), incidence of any adverse event potentially associated with opioid withdrawal or rebound was similar across the groups: 1.9%, 1.9%, and 1.2% for placebo, eluxadoline 75 mg, and eluxadoline 100 mg, respectively. In the four-week single-blind withdrawal period of IBS-3002, incidence of any adverse event potentially associated with opioid withdrawal or rebound was similar across the groups: 5.8%, 5.8%, and 6.1% for placebo, eluxadoline 75 mg, and eluxadoline 100 mg, respectively. In the two phase 3 trials, median overall Subjective Opioid Withdrawal Scale scores (16 questions/0–4 scale) were low and similar across the groups: 3, 2, and 3 for placebo, eluxadoline 75 mg, and eluxadoline 100 mg, respectively.
“The message from these findings is that with IBS-D patients taking eluxadoline at therapeutic doses, you don’t have to worry about abuse potential or withdrawal symptoms,” Dr. Fant concluded.
Dr. Fant commented in an interview that, while buprenorphine is centrally active, eluxadoline is not, and very little passes through the blood–brain barrier. “You would need huge amounts to produce a effect,” he said. Also, exposure by alternative routes of administration is expected to be severely limited by the low tamperability and low extractability of eluxadoline tablets. With oxycodone or hydrocodone, withdrawal effects might appear even after just two or three weeks of dosing, he added. However, patients have been on eluxadoline for nearly a year without the emergence of withdrawal symptoms upon discontinuation.
Efficacy and Safety of Induction Therapy with the Selective IL-23 Inhibitor BI 655066 in Patients With Moderate-to-Severe Crohn’s Disease: Results of a Randomized, Double-Blind, Placebo-Controlled Phase II Study
The interleukin-23 (IL-23) pathway has been implicated both genetically and biologically in the pathogenesis of Crohn’s disease. BI 655066, a humanized monoclonal antibody that selectively inhibits IL-23 through specific targeting of the IL-23 subunit, was the subject of a randomized phase 2 study conducted among patients with moderate-to-severe Crohn’s disease. The patients (n = 121) had clinically active Crohn’s disease (CD Activity Index [CDAI] score of 220 or higher) confirmed by endoscopy (CD Endoscopic Index of Severity score of 7 or higher [4 or higher for patients with isolated ileitis]) and had been treated previously with a tumor necrosis factor antagonist or conventional therapy. They were randomized double-blind to either 200 or 600 mg intravenous BI 655066 or placebo at weeks 0, 4, and 8. The primary endpoint was clinical remission (CDAI of less than 150) at week 12. The study included an induction period, a reinduction/washout period, and a subcutaneous maintenance period.
Clinical remission was achieved by 24.4% and 36.6% of patients with 200 mg and 600 mg of BI 655066, respectively, compared with 15.4% of patients with placebo (P = 0.308 and P = 0.025) in interim results after 12 weeks. Clinical response rates were 36.6% and 41.5% in the 200-mg and 600-mg BI 655066 arms, compared with 20.5% in the placebo group (P = 0.103 and P = 0.037). Endoscopic remission was achieved by 14.6% and 19.5% of patients with 200 mg and 600 mg of BI 655066, compared with 2.6% of patients with placebo (P = 0.056 and P = 0.017). Endoscopic response was achieved by 26.8% and 36.6% of patients with 200 mg and 600 mg of BI 655066, compared with 12.8% of patients with placebo (P = 0.117 and P = 0.014). Deep remission (clinical and endoscopic) was achieved by 2.4% and 12.2% of patients receiving 200 mg and 600 mg of BI 655066, respectively (P = 1.0 and P = 0.062), and for zero patients in the placebo group.
“This underscores how difficult to treat this population was,” Dr. Bocher commented in an interview.
While adverse events were similar among all treatment groups, discontinuations related to adverse events were more frequent in the placebo group and least frequent in the higher-dose BI 655066 group (15.4%, 12.2%, and 2.4%, respectively).
“In patients with active Crohn’s disease, selective blockade of IL-23 with BI 655066 was more effective than placebo for inducing clinical and endoscopic remission at 12 weeks and was well tolerated,” Dr. Feagan concluded.
A phase 3 trial is in the planning phase, according to Dr. Böcher.