Emerging Targets for Hepatitis C -Part 1

Posted on by

The latest advances in hepatitis C are related in several recent publications:

  1. Hepatology 2013; 57: 2143-54.
  2. Hepatology 2013; 57: 2155-63.
  3. Clin Gastroenterol Hepatol 2013; 11: 612-619.

The first two studies provide specific information about the effectiveness of Faldaprevir combined with peginterferon alfa-2a/ribavirin (PEG/RBV) in treatment-naive patients and patients with prior nonresponse respectively.  The third reference provides the big picture regarding all of the emerging treatments.

In the first study, the “SILEN-C1” phase 2 trial, 429 patients without cirrhosis were randomized to several treatment arms.  423 of the 429 patients were genotype 1.  This large study involved 89 centers in 15 countries.  All of the treatment groups received PEG/RBV along with either placebo, faldaprevir 120 mg with lead-in (LI), faldaprevir 240 mg LI and faldaprevir 240 mg without LI.   Faldaprevir is a NS3/4A protease inhibitor which can be administered orally once a day.  Results: SVR achieved in 56% (placebo), 72% (faldaprevir 120mg LI), 72% (faldaprevir 240 mg LI), and 84% (faldaprevir 240 mg without LI).  Discontinuation rates were 1%, 4%, 11%, and 5% for the aforementioned treatment groups.

In the second study, the “SILEN-C2” trial, 290 non cirrhotic genotype 1 patients with either no response or partial response to previous treatment underwent a 48 week treatment trial with a similar design as the SILEN-C1. Results: SVR rates among partial responders were 32% (faldaprevir 240 mg LI), 50% (faldaprevir 240 mg without LI), and 42%(faldaprevir 240 mg BID/LI).  Among null responders, SVR rates were 21% (faldaprevir 240 mg LI), 35% (faldaprevir 240 mg without LI), and 29% (faldaprevir 240 mg BID/LI).  Adverse reactions were higher in those on higher doses and included anemia, rash, indirect hyperbilirubinemia, and nausea. Discontinuation rates were 6%, 4%, and 23% for the aforementioned treatment groups.

The third study provides a landscape of current treatment and emerging treatments.  Given the improvement in SVR among genotype 1 patients, the use of either telaprevir or boceprevir in combination with PEG/RBV is the “new standard of care” among adult patients with HCV.  Studies supporting telaprevir include the ADVANCE study, the REALIZE trial, and the OPTIMIZE study.  For boceprevir, its effectiveness was demonstrated with SPRINT-2, and RESPOND-2.

Both boceprevir and telaprevir, are NS3/4A serine protease inhibitors and are considered direct acting antivirals (DAAs). On the horizon:

  • Simeprevir -NS3/4A protease inhibitor.  Studies: PILLAR, ASPIRE.  SVR: 75-86% in treatment-naive patients. Once daily, no rash or increased anemia.  Hyperbilirubinemia can occur.
  • Faldaprevir -see above studies.
  • Danoprevir -NS3/4A protease inhibitor. Study: DAUPHINE. For genotypes 1 and 4. 100% SVR in genotype 4.  Rates of withdrawal with danoprevir were similar to placebo.
  • Daclatasvir -NS5A replication inhibitor. Study: COMMAND-1. For genotypes 1 and 4.
  • Sofosbuvir -NS5B polymerase inhibitor. Studies: PROTON, ATOMIC. For genotypes 1, 4, and 6.
  • Multiple DAAs in combination. Studies: MATTERHORN, INFORM-SVR, AVIATOR, ELECTRON, SOUND-2

Related blog posts:

What is Gluten-Free?

Posted on by

An excerpt from the National Foundation for Celiac Awareness Press Release:

NFCA Press Release about FDA Gluten-Free Labeling Rule

AMBLER, Pa. (August 2, 2013) – The National Foundation for Celiac Awareness (NFCA), a national non-profit organization dedicated to increasing diagnoses and improving quality of life for those with gluten-related disorders, is responding promptly to the U.S. Food & Drug Administration’s (FDA) final rule on gluten-free labeling by announcing new resources for gluten-free consumers to understand the federal regulations.

“For years, gluten-free labels have gone unregulated, putting our gluten-free community in danger,” said Alice Bast, President of NFCA. “We applaud the FDA for finally publishing a standard definition of gluten-free.”NFCA logo

The new regulations state that a food must contain less than 20 parts per million (ppm) of gluten in order to bear a “gluten-free” label. Researchers support less than 20 ppm as a safe threshold for a product to be consumed by individuals with celiac disease and other gluten-related disorders.

“Evidence-based research conclusively supports the 20 ppm level as a safety threshold for gluten-free products,” said Dr. Alessio Fasano, Director of the Center for Celiac Research at MassGeneral Hospital for Children in Boston. “We welcome the new FDA regulations, which will bring us in line with gluten-free labeling regulations for millions of people around the world.”

Related Links:

Thanks to Kayla Lewis for forwarding the press release.

 

TNF Antagonists and Psoriasis

Posted on by

Using data from the adverse event reporting system (AERS) from the FDA, the authors of a recent report identified a large number of psoriasis rashes which developed among patients receiving tumor necrosis factor α (TNF) antagonists (Inflamm Bowel Dis 2013; 19: 1164-72).

From more than 13 million AERS reports (2004-2011), a total of 5432 reports of psoriasis were noted: 1789 for infliximab, 3475 for adalimumab, and 168 for certolizumab compared with 88 for a control group which consisted of the following medications: propranolol, melamine, and lithium. While the absolute number for certolizumab is lower, the relative risk is similar to infliximab when adjusted for frequency of usage.

The AERS database relies on voluntary reporting and there are numerous reporting biases.  Given that AERS captures only a fraction of all true adverse events, the authors extrapolate that more 15,000 psoriasisiform adverse events occur each.  They note that these reactions typically occur in individuals without a personal or family history of psoriasis.  The onset is variable, but typically occurs 9-11 months after initiating therapy.

Additional references:

  • -IBD 2011; 17: 2512.  n=50.  Skin reactions with adalimumab.  62% of pts develop skin reactions: eczema, acne-like dermatitis, psoriasis-like (6 of 50).  Adalimumab d/c’d in 22%.
  • -JPGN 2010; 52: 230. 6 of 73 pts (8%) developed IFX-induced psoriasis -managed with topical Rx.
  • -Clin Gastro & Hep 2010; 8: xxiv. Image of psoriaform rash assoc with infliximab
  • -Aliment pharmacol Ther 2009; 29: 921-27. Review of psoriaform rash assoc with infliximab. Majority improved when TNF stopped.  Options: Rx w steroids for 3 days around Rx or add MTX.
  • -NEJM 2009; 361: 496. Review of psoriasis.

Unrelated link:

For those of you who do not have teenage sons, perhaps you are not familiar with Jimmy Kimmel’s:  This Week in Unnecessary Censorship – YouTube

What to do with ALTEs?

Posted on by

While apparent life-threatening events (ALTEs) in infants are quite disturbing, the best management for these events is far from clear. A recent systematic review of ALTEs in infants was undertaken and included studies from 1970-2011 (J Pediatr 2013; 163: 94-9). The authors ultimately identified 37 relevant studies: 18 prospective observational studies and 19 retrospective observational studies.

Results:

  • None of the 37 studies yielded “a high level of evidence for diagnostic or prognostic investigations.”
  • Risk factors for ALTE: prematurity, previous ALTEs, and suspected child maltreatment.
  • Routine screening for gastroesophageal reflux, meningitis, bacteremia, and seizures are “highly unlikely to be helpful in patients who are well-appearing and have no other findings suggestive of a diagnosis.”
  • Testing for GERD “is unnecessary in children with ALTEs.”  “A positive test does not necessarily inform management because causation cannot be established.”  Patients with recurrent ALTEs “may benefit from pH monitoring in combination with symptom recording.

Additional references:

NASPGHAN Consensus guidelines on GERD (2009)

Link: Gastroesophageal Reflux Disease in the Pediatric … – NASPGHAN.o

  • In premature infants, a relationship between GER (i.e. reflux) and pathologic apnea and/or bradycardia has not been established.Despite a lack of convincing evidence, if pathological apnea occurs in the face of pre- existing reflux, then the following two statements are the most common features:
  • Although reflux causes physiologic apnea, it causes pathologic apneic episodes in only a very small number of newborns and infants.
  • When reflux causes pathological apnea, the infant is more likely to be awake and the apnea is more likely to be obstructive in nature.
  • A diagnosis of an acute life-threatening event (ALTE) warrants consideration of causes other than GER (i.e. reflux).Reflux of gastric acid seems to be related to ALTEs (episodes of combinations of apnea, color change, change in muscle tone, choking, and gagging) in < 5 % of infants with ALTE. 
  • -J Pediatr 2009; 155: 516. Bradycardia not improved in preemies treated for GER. n=18. Editorial 464 urges not using GER Rx in neonates –outside clinical trials.
  • -J Pediatr 2009; 154: 374. Apnea associated with reduction in LES tone in premature infants; therefore, GER may be secondary to apnea rather than the reverse. Small study -12 apneic event in 7 infants.
  • -J Pediatr 2008; 152: 365. Compared risk factors with SIDS. One of 153 (0.6%) with ALTE died.
  • -Pediatrics 2005; 116: 1059 & 1217 (editorial). Apnea in preemies is unrelated to GER.
  • -Pediatrics 2004; 113: e128-132. Apnea is unrelated to GER in most preemies; airway problems due to GERD is hard to establish.
  • -J Pediatr 2000; 137: 321 & 298. Poor temporal association between GER & apnea in ALTE patients.
  • -J Pediatr 2001; 138: 355. Metoclopropramide/cisapride do not help apnea in preemies with GER
  • -Pediatrics 2002; 109: 8-11. GER does not cause apnea of prematurity.

Saving Livers and Saving Lives -An Insider’s View

Posted on by

Pediatric Hepatology hep26580

The link above provides a terrific overview (Hepatology 2013; 58: 458-476) of the development of pediatric hepatology as a subspecialty.  For someone who was incredibly fortunate enough to train in the mid-1990s (right place, right time, right colleagues), I enjoyed finding out more about the decades that preceded my fellowship.  In addition, the article provides insight into the personal background of one of my mentors (thanks for Figure 1) and about a few patients that provided the clinical challenge for furthering the understanding of the pathophysiology of hepatobiliary disorders.

Remission in Crohn’s Disease

Posted on by

A recent article highlights the issue of remission in Crohn’s disease (CD) (Inflamm Bowel Dis 2013; 19: 1645-53).

As noted in previous blog entries (see links below), improvements in remission with ImproveCareNow and with previous drug trials have several limitations due to the current definition of remission.  Currently, even during periods of clinical remission (defined currently mainly by symptoms), laboratory or endoscopic evidence of persistent inflammation can be seen.  Persistent inflammation is likely to lead to progressive bowel damage. With the advent of more effective treatments as well as better biomarkers, a more objective measure of remission is needed.

“Remission is an evolving concept in CD. At its most fundamental level, remission should be a state with little or no risk of disease progression, likely implying the absence of biological evidence of inflammation.”

The authors proposed definitions of remission based on whether the patient has “early” disease or “late” disease.  Early disease “may be defined as disease duration ≤18 months without previous exposure to immunosuppressants or biologics.”

Early disease:

  • Biologic remission (inflammation control): a) mucosal healing on colonoscopy (no ulcers with the exception of a few aphthous ulcers <5 mm in diameter) and/or b) improvements in serum and fecal biomarkers: CRP < 5 mg/L, fecal calprotectin <250 mcg/g
  • Clinical remission in practice (symptom control): complete absence of symptoms; 1-2 formed stools per day without abdominal pain.  In a clinical trial, CDAI <150 points.
  • Outcomes: no disease progression or complications, normal quality of life

Late disease:

  • Biologic remission (inflammation control): a) mucosal healing on colonoscopy (no ulcers with the exception of a few aphthous ulcers <5 mm in diameter) and/or b) improvements in serum and fecal biomarkers: CRP < 5 mg/L, fecal calprotectin <250 mcg/g
  • Clinical remission (symptom control): a: inflammatory symptom improvement (may have residual symptoms due to previous damage or surgery). In clinical trial, CDAI 150-220 points.
  • Outcome: stabilization of noninflammatory symptoms and no progression of structural damage, improved quality of life

The authors goal is to rework remission to include symptom control and histologic/mucosal healing.  This concept is not novel.  Investigators in the adalimumab EXTEND study coined the term “deep remission.” This term referred to patients with both CDAI remission and complete mucosal healing.  Patients who achieved deep remission had improved outcomes, including fewer hospitalizations and fewer surgical resections (Gut 2010; 59: A80).

Bottomline: Improvements in both objective measures of biologic inflammation along with resolution of clinical symptoms are needed to change the long-term outcome for patients with Crohn’s disease.  The definition of remission should reflect this reality.

“When you can measure what you are speaking about and express it in numbers, you know something about it; but when you cannot express it in numbers, your knowledge is of a meagre and unsatisfactory kind” –Lord Kelvin 1883

Related blog entries:

Fewer Intern Hours & No Change in Patient Safety

Posted on by

Excerpt from Gastroenterology & Endoscopy News (Shorter Workweeks for Interns Do Not Promote Patient Safety) :

A policy to shorten the workweek for interns in the United States has failed to improve their quality of life and has possibly put patients at greater risk for medical errors, a new study has found (Sen S et al. JAMA Intern Med 2013;173:657-662).

The 2011 policy change, recommended by the Accreditation Council for Graduate Medical Education, capped at 16 continuous hours the longest shift a first-year resident could work in the hope that doing so would ease the strain on physician trainees.

But although the new rules have shortened the typical intern’s workweek from 67 to 64.3 hours, they haven’t encouraged residents to sleep more, helped them to avoid depression or increased their overall sense of well-being, the study found…The study was based on email surveys of 2,323 residents …entered training in 2009, 2010 and 2011, after the rule change.

“Given that increased sleep was a key [mechanism] through which the new duty-hour restrictions were intended to improve the health of residents, the lack of such an effect in the postimplementation cohort in our study is a cause for concern,” wrote the authors, led by Srijan Sen, MD, PhD, a psychiatrist at the University of Michigan in Ann Arbor. “Designing work schedules that account for circadian phase and explicitly training residents on practices to increase sleep time and improve sleep quality may be necessary.”

Ketamine for chronic pain –is this a good idea?

Posted on by

A recent phase 1 study explored the use of oral ketamine for chronic pain (J Pediatr 2013; 163: 194-200).

Ketamine has several mechanisms of actions in improving pain.  It is frequently used in emergency room settings because of its analgesic and dissociative amnestic qualities.  In addition, it has relatively little cardiorespiratory impact, a short half-life, and is better tolerated in children than adults.

Given the frequency of chronic pain in children and the relative paucity of treatment options, the authors aimed to determine whether ketamine in a short-term study (2 weeks) would be safe and effective.  This prospective study enrolled 12 patients who received ketamine 3 times per day at dosages of 0.25-1.5 mg/kg/dose .**

Pain diagnoses included chronic pancreatitis, Crohn’s disease, esophageal spasm, headache, joint pains, and other causes.  Median age was 16 years (range 11-19).

Results:

  • Two participants, both treated with 1.5 mg/kg/dose, experienced dose-limiting toxicities: sedation and anorexia.
  • Of the 12 patients, 5 had improvement in pain scores; 2 of these patients had complete resolution of pain which lasted >4 weeks off ketamine treatment.
  • There was evidence of norketamine accumulation in many patients.  Norketamine is the major metabolite of ketamine.

**Note: All medication dosages should be checked in standard references for individual patients.  This blog may have transcription errors with regard to dosages.

Related blog posts:

More breastmilk, better development

Posted on by

A recent study further explored breastmilk’s effect on infant cognitive and motor development in the French EDEN Mother-Child Cohort Study (J Pediatr 2013; 163: 36-42).

The authors acknowledge that previous studies have shown that breastfed children have  higher scores at tests on cognitive abilities; “however, some authors suggested that these results were due to the difference between the socio-demographic and occupational characteristics of mothers who breastfed and those who did not.”  Though, a large randomized trial (Arch Gen Psychiatry 2008; 65: 578-84) showed convincing data that a  longer duration of exclusive-breastfeeding duration improved children’s cognitive development.

So why did the authors bother with this study? The authors note that few studies have been performed in France where breastfeeding is less common than other European countries and their object of showing a dose-response relationship would further the arguments for causality.

Design: 1387 two-year-olds and 1199 three-year-old children were assessed from the EDEN cohort (2002 pregnancies) which prospectively collected data at birth, 4 months, 8 months,   1 year, and 2 years.

Results:

  • After adjusting for many confounding factors, infants who had breastfed scored 3.7 points higher on the Communicative Development Inventory (CDI) than infants who had never breastfed.
  • Longer breastfeeding duration was associated with better cognitive and motor development in 2- and 3-year-old children.  Each additional month of breastfeeding was associated with an increase of 0.75 CDI points and 1.00 in the Ages and Stages Questionnaire (ASQ).

Take-home message: Most studies, including the present, have shown benefits of breastfeeding on infant development.  In addition, there is likely a dose-response relationship.

Related blog posts:

Rethinking top-down treatment?

Posted on by

Given the effectiveness of biologic therapy and the potential for disease modification, the threshold for “top-down” treatment has been lower at this time as compared with “step-up” treatment.  What about long-term outcomes, does starting soon increase or decrease the likelihood of doing well?  A recent study suggests that “early biologic therapy did not improve disease activity or quality of life” (Inflamm Bowel Dis 2013; 19: 1397-1403).

In this retrospective chart review involving 93 patient’s with Crohn’s disease (between 2004 and 2010), patients whose data was prospectively maintained were categorized into either early biologic therapy or a step-up group. For these patients, the mean age at diagnosis was 28 years.  There were no apparent differences in demographic variables between the groups; however, the early biologic therapy group had higher disease activity and lower quality of life scores at baseline. 20% were current smokers and 61% never smoked.  Disease location was similar in both groups; overall, 35% had ileal disease, 13% colonic disease, 34% ileocolonic, and 7% isolated upper tract disease.

Results:

  • Mean Harvey-Bradshaw index and Short Inflammatory Bowel Disease Questionnaire scores at 3, 6, and 12 months were not different between the groups.
  • Early biologic therapy group had more hospitalizations.
  • No difference in steroid use or surgeries was noted at one year.

Take-home message: This study suggests that differences in outcomes between “top-down” therapy and step-up therapy are more pronounced early in the treatment course but may wane after 1 to 2 years.  However, early biologic therapy “may be a more effective strategy in patients with Crohn’s disease with higher disease activity.”

Relating blog posts: