Coming Soon to a Pharmacy Near You (part 1)…

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Vedolizumab!

Two articles indicate that Vedolizumab will be an important agent for treating Ulcerative Colitis (UC).  The first article, NEJM 2013; 369: 699-710, describes two integrated studies (GEMINI 1 studies) in the use of this agent for induction and then for maintenance therapy of UC.

Background: Vedolizumab is a gut-selective blocker of lymphocyte trafficking (see previous post: Vedolizumab -another new IBD treatment | gutsandgrowth).  It is similar to natalizumab which was approved in 2008 for Crohn’s disease.  In phase 3 trials, natalizumab was demonstrated a response in 48% of patients with moderate-to-severe disease, but its large-scale use has been precluded by the potential for reactivation of the John Cunningham (JC) virus and progressive multifocal leukoencephalopathy (PML).

Study design: this study was a phase 3, randomized, double-blind, placebo-controlled study conducted at 211 medical centers in 34 countries from 2008-2012.  At baseline some of the assessments included blood tests, stool for enteric pathogens, chest radiography, stool calprotectin, QuantiFERON-TB Gold assay and sigmoidoscopy.  Intravenous vedolizumab was administered at a dose of 300 mg or placebo at days 1 and 15 during induction; also patients were stratified for glucocorticosteroids, use of immunosuppressives and prior use of TNF antagonists.  In total, 746 patients received vedolizumab and 149 received placebo.

Some of the baseline patient characteristics:

  • Mean age: 40.3 yrs
  • Median prednisone dose: 20 mg
  • Average fecal calprotectin: 899 mcg/gr.
  • Site of disease: 37% pancolitis, 13% rectum/sigmoid only, 37.9% left-sided disease, 12.2% disease proximal to splenic flexure.
  • Prior anti-TNF therapy: 48.2%

Results:

  • Induction: at week 6, 47.1% of vedolizumab and 25.5% of placebo-treated patients had a clinical response
  • Maintenance: at week 52, of patients randomly assigned to continue receiving vedolizumab, 44.8% every 4 weeks, 41.8% every 8 weeks were in clinical remission compared with 15.9% receiving placebo
  • Glucocorticoid-free remission at 52 weeks in 45.2% of patients receiving vedolizumab every 4 weeks, 31.4% receiving every 8 week treatment, and 13.9% of placebo-treated patients.
  • Figure 1 details important changes in Partial Mayo score, IBDQ score, Fecal calprotectin, and prednisone dose changes.  With regard to fecal calprotectin, at week 6 the median calprotectin level had dropped approximately 70%.  Smaller decreases were noted in patients continuing vedolizumab at week 52.
  • Safety: “no important differences” according to the authors between vedolizumab and placebo.  Specifically, there were no cases of PML; however, routine JC virus testing was not performed in this study.  Infusion reactions were seen in three cases (two with detectable antibody). a mild increase in nasopharyngitis was noted.
  • Cancer: 1.1% of placebo-treated patients developed a malignancy (1 colon cancer, 1 transitional-cell carcinoma, 1 squamous-cell carcinomas of skin) and 0.2% of vedolizumab (1 colon cancer)
  • Drug levels: mean vedolizumab concentrations at every 4 week dosing: 38.3 mcg/mL and at every 8 week dosing: 11.2 mcg/mL
  • Antibodies: 3.7% had samples that were positive for anti-vedolizumab antibodies at any time.  1% developed persistent antibody positivity.

Bottom-line: This large study shows that vedolizumab is effective in a large number of patients with UC, many who were refractory to other treatments, including anti-TNF agents.

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Looking at the Tenofovir Data Another Way

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In last Friday’s post, this blog reviewed 5-year data on tenofovir usage which showed that tenofovir could reverse fibrosis/cirrhosis.  Another study using the same cohort examined the efficacy of tenofovir in patients with high viral load (HVL) at baseline (Hepatology 2013; 58: 505-13).

From an initial total of 641 patients enrolled in GS-US-174-0102 (n=375) and GS-US-174-0103 (n=266), the authors identified 129 (20%) with HVL.  HVL was defined as having ≥9 log10 copies/mL.  After an initial 48 weeks of randomization between tenofovir (HVL n=82) or adefovir (HVL n=47), patients received an additional 192 weeks of therapy with tenofovir in an open label extension.

Results:

  • By week 240, 98.3% of HVL and 99.2% of non-HVL patients on treatment achieved HBV DNA <400 copies/mL
  • High HVL patients took longer to achieve undetectable HBV DNA, but by week 96 the results were similar in both groups
  • Patients who received tenofovir during the initial 48 weeks achieved undetectable HBV DNA quicker than those who had received adefovir initially
  • There were similar rates of histologic regression in both HVL and non-HVL patients

This study evaluated only patients in the ‘immune clearance’ phase of HBV and therefore cannot be extrapolated to those in the immune tolerant phase.

Injection Flu Vaccine Safe for Patients with IBD

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A recent article from Pediatrics, published online May 6, 2013
(doi: 10.1542/peds.2012-3567), confirms that influenza vaccination (injection/inactivated vaccine) is safe in patients with inflammatory bowel disease:

“Safety and Utilization of Influenza Immunization in Children With Inflammatory Bowel Disease”  Eric I. Benchimol, Steven Hawken, Jeffrey C. Kwong, and Kumanan Wilson

Abstract:

OBJECTIVE: Influenza immunization is recommended for children with IBD, however safety concerns may limit uptake. This study assessed whether immunization was associated with adverse events in IBD patients using a population-based database of children with IBD.

METHODS: All children <19 years diagnosed with IBD in Ontario, Canada between 1999–2009 were identified using health administrative data, and matched to non-IBD controls. Self-controlled case series (SCCS) analyses determined health services event rates (outpatient visits, hospitalizations and emergency visits) in any 2-week risk period to 180 days post-immunization compared to a no-risk control period. Relative incidence (RI) was calculated for overall and IBD-related events and rates were compared between IBD cases and controls using relative incidence ratios (RIR).

RESULTS: 4916 IBD patients were matched to 21,686 controls. IBD patients were more likely to have received immunization than controls (25.3% vs. 13.2%, P < .001). No increased event rates existed in IBD cases during risk periods (pooled RI 0.95, 95% CI 0.84–1.07), including hospitalizations and emergency visits. There was a slightly higher event rate in IBD cases versus controls for days 3–14 (RIR 1.60, 95% CI 1.05–2.44, P = .03). IBD-related visit rates were lower in risk periods compared to control period (pooled RI 0.81, 95% CI 0.68–0.96).

CONCLUSIONS: There was no increase in health services use in the post-vaccine risk period in IBD patients, and there was evidence for a protective effect of influenza immunization against IBD-related health services use. Influenza immunization is safe in children with IBD and should be encouraged to improve poor coverage rates.

Gluten-free, Casein-free -No Improvement in Autism

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From Kipp Ellsworth’s twitter feed:

The gluten-free, casein-free diet and autism: limited return on family investment

From Journal of Early Intervention

goo.gl/uulzis  (link to entire article)

Excerpt:

Abstract

The gluten-free, casein-free (GFCF) diet is widely used by families of children with autism spectrum disorders (ASD). Despite its popularity, there is limited evidence in support of the diet. The purpose of this article was to identify and evaluate well-controlled studies of the GFCF diet that have been implemented with children with ASD. A review of the literature from 1999 to 2012 identified five studies meeting inclusion criteria. Research rigor was examined using an evaluative rubric and ranged fromAdequate to Strong. In three of the studies, no positive effects of the diet were reported on behavior or development, even after double-blind gluten and casein trials. Two studies found positive effects after 1 year but had research quality concerns. Reasons why families continue to expend effort on GFCF diets despite limited empirical evidence are discussed. Recommendations are that families should invest time and resources in more robustly supported interventions and limit GFCF diets to children diagnosed with celiac disease or food allergies.

Changing the Outcome for Hepatitis B

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Much of hepatology relies on surrogate markers to convey whether treatments are effective.  For hepatitis B virus (HBV), some of these markers include serology (eg. development of HBV e antibody), improvements in biochemistry (eg. transaminases) as well as histology.  Of these, improved histology is likely to have the most bearing on clinical outcomes like progression to end-stage liver disease and hepatocellular carcinoma.  A previous study of lamivudine has indicated that regression of fibrosis can reduce the rate of hepatocellular carcinoma (NEJM 2004; 351: 1521-31).

As such, the results of long-term use of agents like tenofovir have been awaited.  Since tenofovir along with entecavir are considered 1st line agents, their use has become commonplace for the treatment of HBV.  Now 5-year data are available in a large cohort (Lancet 2013; 381: 468-75).

The data from this study was derived from an open-label cohort that followed 48-week double-blind comparison trials. 489 patients completed 240 weeks of treatment.  348 patients had biopsy results available at baseline and at week 240.

Key findings:

  • 304 (87%) of those with biopsies at study completion had histologic improvement.
  • 176 (51%) had regression of fibrosis
  • 71 of 96 (74%) who had cirrhosis at baseline no longer had cirrhosis (≥1 unit decrease in Ishak fibrosis score)
  • 3 of 252 without cirrhosis at baseline progressed to cirrhosis at week 240
  • No evidence of resistance to tenofovir was evident.  Nearly all patients on tenofovir had undetectable HBV DNA
  • Adverse safery events were rare

As with all studies looking at liver histology, there were limiting factors including potential sampling errors and variable interpretation.  The authors sought to minimize this by using an independent pathologist.   Another strength of the study was the broad range of patients to make these findings broadly applicable.

Take-home message: Tenofovir treatment for 5 years is safe and effective.  Long-term suppression of HBV can lead to regression of fibrosis and reversal of cirrhosis.

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Fundoplication in children with neurologic impairment

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A recent study questions the value of fundoplication in children with neurologic impairment who undergo gastrostomy tube placement (JAMA Pediatr doi:10.1001/jamapediatrics.2013.334).

This paper’s findings are limited by the study’s design as a retrospective, observational cohort study.  However, the study has several strengths as well.  First of all, this was a large study which identified 4163 neurologically-impaired infants who underwent either tube placement with (n=1404) or without fundoplication (n=2759).  This population was drawn from 42,796 infants admitted to neonatal intensive care units from 42 children’s hospitals.  Thus, a second advantage of this study was looking at a broad range of children from the same NICU population.

Findings:

  • Infants who underwent fundoplication did not have a reduced rate of reflux-related hospitalizations.  The authors tried to control for differences in the population with propensity score-matched analysis.
  • Only a small number had a significant preoperative GERD workup.  In total, 9.4% of infants had pH probes and 4.3% had endoscopies preoperatively.
  • Mean number of reflux-related admissions (Table 3 in study) within 1 year after discharge from NICU: overall: for gtube 0.92 compared with 1.02 for gtube/fundo, for pneumonia 0.18 (Gtube) compared with 0.23 (Gtube/fundo), aspiration pneumonia was 0.08 for both groups.

The authors note that two previous studies had shown a reduction in reflux-related hospitalizations for children who had admissions due to reflux-related conditions.  However, they note that in their study, these patients had fundoplication performed prophylactically based on clinical judgement.

But, “clinical symptoms, including dysfunctional swallowing and intolerance of gastric feedings, likely influence the decision to perform a concomitant fundoplication; however, these were unavailable in the database.”  As such, the authors propensity score model could have failed to account for factors that are essential in deciding whether a concomitant fundoplication is worthwhile.

Bottom-line: A fundoplication may not effectively prevent reflux-related hospitalizations in neurologically-impaired infants; its expected benefits may be overstated.  The only way to definitively determine how useful (or how ineffective) a fundoplication is would be a prospective study.

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Big Interferon-free Hepatitis C Study

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Every week there is more information on clinical trials for hepatitis C; I am waiting for this to translate into improvements for the pediatric population.

This week’s biggest publication: NEJM 2013; 369: 630-9.  This was a phase 2b randomized open-label trial of faldaprevir (a NS3/4A protease inhibitor) in combination with deleobuvir (a non nucleoside NS5B polymerase inhibitor).  In total, 5 different regimens were examined, most in combination with ribavirin.  The authors recruited 362 HCV genotype 1 patients who were randomized into these treatment groups & he sustained virologic response 12 weeks after completion of therapy

  • Faldaprevir 120 daily, deleobuvir 600 three times a day, and ribavirin for 16 weeks (TID16W) –>59%
  • Faldaprevir 120 daily, deleobuvir 600 three times a day, and ribavirin for 28 weeks (TID28W) –>59%
  • Faldaprevir 120 daily, deleobuvir 600 three times a day, and ribavirin for 40 weeks (TID40W) –>52%
  • Faldaprevir 120 daily, deleobuvir 600 two times a day, and ribavirin for 28 weeks (BID28W) –>69%
  • Faldaprevir 120 daily, deleobuvir 600 three times a day, without ribavirin for 28 weeks  (TID28W-NR) –>39%

Rates of SVR were higher among genotype 1b, 56-85%, compared with 1a, 38-43% (when excluding non-ribavirin group).  Genotype 1a patients with IL28B CC had similar response (58-84%) to genotype 1b patients.  Genotype 1a patients were much more likely to relapse if not treated for at least 28 weeks.

Adverse effects were common and reported in 94% of participants; 9% had severe adverse reactions.  Gastrointestinal and dermatologic advents events were the most frequent.  Also, faldaprevir resulted in jaundice (unconjugated hyperbilirubinemia) in many patients (16-28% of patients who took ribavirin in their regimens).

This large study showed that when these oral antiviral are used in combination with ribavirin that results are similar to current standard of care treatments for adult patients.  For telaprevir or boceprevir, along with pegylated interferon and ribavirin, phase 3 trials showed SVRs between 68-75%.

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Gastrostomy Tubes for Children with Cystic Fibrosis

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A recent report indicates that gastrostomy tubes (Gtubes) can be safe and useful for supplemental nutrition in children with cystic fibrosis (CF) and portal hypertension (JPGN 2013; 57: 245-47).

This small study from Australia was a retrospective study of their CF database from 1991-2011.  During this timeframe, 60 CF patients had gastrostomy tubes.  7 children had CF and portal hypertension.  The mean age of insertion was 10.6 years and all of these patients were pancreatic insufficient. Six of these 7 patients had percutaneous endoscopic gastrostomy (PEG); one had open surgical placement due to preexisting varices.  The median length of followup was 4 years.

Results:

  • No patients developed stomal varices
  • One patient had minimal cellulitis in the perioperative period, otherwise no complications were noted.
  • Two patients died related to advanced pulmonary disease
  • Three patients developed varices during the course of their care
  • Overall, there was improvement in BMI z-score at 2 years from -1.07 ± 0.87 to -0.58 ± 0.81 (p=0.05) and also at w years there was improvement in pulmonary function in 6 patients with mean FEV-1 going from 49.5 ± 12.6 to 62.3 ± 20.3 (P=0.04)

Take-home message: in a select group of 7 patients with Cystic Fibrosis and portal hypertension, gtube placement was safe and associated with better nutrition and lung function.

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Data on Chelators for Wilson Disease

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A recent retrospective analysis on 405 patients with Wilson disease analyzed the efficacy and safety of oral chelators for Wilson disease (Clin Gastroenterol Hepatol 2013; 11: 1028-35).

The authors noted that there were frequent changes in medication; in total, 471 monotherapies were analyzed: 326 patients with D-penicillamine (DPA) and 141 with trientine.  Trientine was a first line treatment in only 38 patients.  About 50% of patients presented with hepatic symptoms, about 20% neurologic symptoms, about 15% with combined hepatic/neurologic symptoms and the remainder, ~10%, were asymptomatic.

  • 9 of 326 with DPA and 3 of 141 with trientine underwent liver transplantation.
  • Adverse effects were more common with DPA, including arthralgias (8.9%), proteinuria (6.1%), ANA antibodies (6.7%), gastric complaints (2.5%) and polyneuropathy (1.8%).  28.8% of DPA stopped therapy due to adverse effects.
  • Adverse effects with trientine resulted in stopping treatment in 7.1% and included arthralgias in 2.8%, and gastric complaints in 1.4%.
  • Hepatic improvements were observed in >90%

The authors summarize their findings:

“Both DPA and trientine were equally and highly effective in controlling liver disease…In light of recent reports of hepatic deterioration under zinc therapy, the current data emphasize the role of these chelating agents in the treatment of symptomatic hepatic patients.”

Related blog post:

Finding the Right Specialist | gutsandgrowth This post has link to AASLD guidelines for Wilson disease.

POEMs in Practice for Achalasia

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As noted in a previous blog  regarding NOTES (see link below), peroral endoscopic myotomy (POEM) has been investigated for treatment of achalasia.  Now, a prospective study of 70 patients from 5 centers reports excellent results (Gastroeenterol 2013; 145: 309-11, editorial 272-73).

 Results:

  • 3 months after POEM, 97% of patients were in symptom remission.
  • 12 months after POEM, 82% of patients were in symptom remission.

Potential benefits of POEM:

Early results suggest similar efficacy to surgery but with the recovery profile of an endoscopy Painless

For more widespread adoption, many questions need to addressed:

  • the appropriate length & thickness of myotomy
  • the optimal equipment
  • the best ‘surgeons’ for this technique
  • how do long-term outcomes compare to Heller myotomy or balloon dilatation

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