Changing Narrative on Affordability of HCV Treatments

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A recent commentary (J Chhatwal et al. Clin Gastroenterol 2015; 13: 1711-13) makes the point that HCV treatment is looking a lot better lately with regard to cost.

Key points:

  • “Sofosbuvir-based treatment in 2015, on average, costs 54% of the wholesale acquisition cost”
  • When considering the recent discounts, “the cost of treatment decreased to $56,000…and the cost per SVR decreased to $58,000.”  The cost of an SVR with the first generation protease inhibitors, boceprevir and teleprevir, has been estimated to have been $213,000.
  • “The discounted cost of treating 1 person with HIV in the United States is $315,000 in 2014 US dollars.” Thus, curing HCV which is more deadly, at 18% of the cost, looks more favorable.
  • More discounts and more competition are expected.

Bottomline: Based on these cost considerations, the authors state that HCV treatment should be used broadly and not solely in those with advanced fibrosis.

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Atlanta Botanical Gardens

Atlanta Botanical Gardens

Down Syndrome -Updated Growth Curves

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Full link to Pediatrics article (www.pediatrics.org/cgi/doi/10.1542/peds.2015-1652 DOI: 10.1542/peds.2015-1652): Growth Charts for Children with Down Syndrome in U.S. (Reference from Kipp Ellsworth)

Excerpt:

New DSGS growth charts were developed by using 1520 measurements on
637 participants. DSGS growth charts for children ,36 months of age showed marked improvements in weight compared with older US charts. DSGS charts for 2- to 20-year-olds showed that contemporary males are taller than previous charts showed. Generally, the DSGS growth charts are similar to the UK charts.

 

Fecal Diversion for Perianal Crohn’s Disease

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A recent study (S Singh et al. Alimentary Pharmacology & Therapeutics; 2015: 42: 783-92; article first published online: 11 AUG 2015. DOI: 10.1111/apt.13356) gives more specific data regarded the outcomes of fecal diversion for perianal Crohn’s disease.  While diversion can be helpful, the meta-analysis indicates that only one-sixth of patients were able to achieve successful bowel continuity/reconnection.  The authors did not note a significant improvement in successful bowel continuity restoration in the era of biologics compared with prebiologic era (17.6% vs13.7%).

An excerpt of a summary of this study from Gastroenterology & Hepatology (September 2015)

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Stranger than fiction?

Stranger than fiction?

Is Autoimmunity Associated with Nonceliac Wheat Sensitivity?

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According to a recent study (A Carroccio, et al. Gastroenterol 2015; 149: 596-603), patients with nonceliac wheat sensitivity (NCWS) (aka. nonceliac gluten sensitivity or wheat intolerance syndrome) are more prone to developing autoimmune disorders compared with patients with irritable bowel syndrome.

Given the difficulty identifying NCWS, the findings must be viewed cautiously; in addition, much of this study was a retrospective study.

Background: The authors identified 131 patients diagnosed with NCWS (121 female) with a mean age of 29 years.  They compared these individuals to control groups of patients with either celiac disease (CD) or irritable bowel syndrome (IBS).  In addition to the retrospective study, the authors prospectively examined 42 patients diagnosed with NCWS (2011-2014).  These diagnoses were established by double-blind placebo-controlled wheat challenge.

Key findings:

  • In the retrospective analysis, 29% of NCWS patients and 29% of CD developed autoimmune diseases (mainly Hashimoto’s thyroiditis, 29 cases) compared with a smaller proportion of subjects with IBS (4%) (P<.001).
  • In the retrospective analysis, 46% of NCWS, 24% of CD and 2% of IBS developed ANA antibodies (median titer 1:80).
  • In the prospective arm, 24% of NCWS, 20% of CD, and 2% of IBS subjects developed autoimmune disease.
  • Similarly, in the prospective arm,  28% of NCWS, 7.5% of CD and 6% of U+IBS developed ANA antibodies (median titer 1:80).
  • ANA positivity was associated with the presence of HLA DQ2/DQ8 haplotypes (P<.001).  ANA positivity, to a lesser extent, was associated with the presence of duodenal lymphocytosis (grade A histology).

The authors note that “these associations strongly suggest a celiac condition, but it must be emphasized that all the patients we included were negative for CD-specific antibodies and showed normal intestinal villi” with a gluten challenge.

Potential limitations included a selection bias of patients referred to this tertiary center.

My take: This study suggests significant overlap between CD and NCWS.  The real frequency of autoimmunity in NCWS is unclear as this study population is not likely representative of most patients who go gluten-free.

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Atlanta Botanical Gardens

Atlanta Botanical Gardens

“Men Sometimes See Exactly What They Wish To See” and Gluten Sensitivity

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For me, a recent study (AD Sabatino et al. Clin Gastroenterol Hepatol 2015; 13: 1604-12, editorial 1613-15) was particularly interesting.  While it had “positive results,” these findings were based almost entirely on the results of three patients.

In brief, this study examined 61 adults (w/o celiac disease) who believed that gluten induced intestinal and extraintestinal symptoms.  These individuals were randomized to receive either 4.375 g/day of gluten or rice starch via capsules.  This amount of gluten is equivalent to 1 sandwich or 2 slices of bread.

Findings:

  • Overall, intake of gluten significantly increased symptoms compared to placebo (P=.034), including bloating, pain, foggy mind, depression, and aphthous stomatitis.
  • Looking at a scatterplot (Figure 4), it is abundantly clear that all of these findings are driven by 3 patients.
  • “In the vast majority of patients the clinical weight of gluten-dependent symptoms was irrelevant in light of the comparable degree of symptoms experienced with placebo”
  • “Our study did not provide any progress in identifying possible biomarkers of NCGS [non-celiac gluten sensitivity]”

This type of study, with mixed conclusions, led the editorialists to quote Spock (from Star Trek):

“In critical moments, men sometimes see exactly what they wish to see.”

Then, the editorial provides a historical context of NCGS with a review of the relevant prior studies.  Other comments:

  • “These findings can be a Rorschach test of sorts, in which the viewer draws interpretations that are  based on his or her prior beliefs about NCGS.”
  • The authors note that both the gluten and the control arm likely had a significant nocebo effect (negative placebo effect),
  • “This trial, like its predecessors, seems only to contribute to the uncertainty about NCGS.”

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Yellowstone Canyon

Yellowstone Canyon

 

Do We Need Lie Detector Tests for Research Participants?

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“Misconduct by research participants is a serious problem” (DB Resnick, DJ McCann. NEJM 2015; 373: 1192-3).

While research deception by investigators receives a great deal of attention, apparently research participants often fabricate or falsify information.  Key points in this commentary:

  • Research participant deception does not violate federal rules or institutional policies.
  • Among a group of 100 participants who had participated in at least two studies, a recent study found that 25% admitted to exaggerating their symptoms in order to qualify and 14% pretended to have a health problem that they did not have
  • Other deceptions: concealing other health problems, enrollment in other studies, prescription drug use, and recreational drug use

Why lie?

  • Economic motives
  • Embarrassment re: sexual history, mental health, or illegal activities

Are there consequences to this deception?

  • By including patients who may be ‘destined to succeed,’ it creates a significant bias and reduces the statistical power and effect size of a research study.
  • Deception could lead to a false conclusion that a drug was not very effective.
  • By including patients who do not have a condition, the true safety of the medication in the target population cannot be determined precisely.
  • Participants may place themselves at risk for complications by withholding important information.  (Example: Bernadette Gillcrist. Hastings Cent Rep 1980: 10: 5-6).

Potential ways to discourage deception?

  • Better screening with exams and blood tests (e.g. assays for non-study medications).
  • Require participants to be listed in a clinical trial patient registry.  The U.S. does not currently have a national registry.

Perhaps, a good first step is to let research candidates understand how their deception can be harmful.  I suspect that many are interested in the inducements to participate without considering the consequences of exaggerating their health problems.

My take: Given the enormous expense involved in most research studies, assuring that the research subjects are appropriate is crucial.  How to achieve this goal is not so clear.

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Atlanta Botanical Garden, Bruce Munro's Dome

Atlanta Botanical Garden, Bruce Munro’s Dome

Gastrointestinal Hemangiomas in Infancy

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A brief study (IW Soukoulis et al. JPGN 2015; 61: 415-20) makes several useful points about gastrointestinal infantile hemangiomas. This study retrospectively analyzed 16 children (14 less than 1 yr) and described the presentation and management of gastrointestinal hemangiomas.

Key points:

  • Most were female (14/16)
  • Melana, hematochezia and anemia were typical presentations, usually within the first 4 months of life
  • 9/16 also ahd some cutaneous hemangiomas.  These lesions were located predominantly in the midgut in the distribution of the SMA. Thus, endoscopy (EGD/colonoscopy) is mainly to exclude other etiologies.
  • Imaging usually will detect these lesions (High-resolution Ultrasound, CT, or MRI)
  • 1st line treatment: Propranolol and/or corticosteroids

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Sandy Springs

Sandy Springs

“More People Than Ever Want To Be Doctors”

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From NBC News: “More People Than Ever Want To Be Doctors”

More people than ever want to be doctors, a new survey shows. Enrollment is up 25 percent this year over 2002, with more black applicants and Hispanic applicants being accepted.

More than 52,000 people applied to medical school in 2015 — up more than 56 percent from 2002 — the survey by the Association of American Medical Colleges (AAMC) found…And 20,630 were enrolled, a 25 percent increase over the 16,488 enrolled in 2002….

“The number of Hispanic or Latino enrollees increased by 6.9 percent to 1,988, and the number of applicants increased by 10.3 percent to 4,839,” the AAMC said in a statement.

“African-American enrollees rose 11.6 percent to 1,576, while the number of applicants increased by 16.8 percent to a total of 4,661.”

Disco is Dead

NY Times: Cutting Sugar Improves Children’s Health in Just 10 Days

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Perhaps this is not the best day of the year for this topic….

A recent small study of 43 children is summarized by the NY Times: Cutting Sugar Improves Children’s Health in Just 10 Days

An excerpt:

Obese children who cut back on their sugar intake see improvements in their blood pressure, cholesterol readings and other markers of health after just 10 days, a rigorous new study found.

The new research may help shed light on a question scientists have long debated: Is sugar itself harming health, or is the weight gain that comes from consuming sugary drinks and foods mainly what contributes to illness over the long term?

In the new study, which was financed by the National Institutes of Health and published Tuesday in the journal Obesity, scientists designed a clinical experiment to attempt to answer this question. They removed foods with added sugar from a group of children’s diets and replaced them with other types of carbohydrates so that the subjects’ weight and overall calorie intake remained roughly the same.

After 10 days, the children showed dramatic improvements, despite losing little or no weight. The findings add to the argument that all calories are not created equal, and they suggest that those from sugar are especially likely to contribute to Type 2 diabetes and other metabolic diseases, which are on the rise in children, said the study’s lead author, Dr. Robert Lustig, a pediatric endocrinologist at the Benioff Children’s Hospital of the University of California, San Francisco.

My take:  For a long time, I have been telling patients that if they make only one change, I would start by eliminating sugar-sweetened beverages. While this is a small study, it reinforces the view that sugar intake needs to be limited.

This post included last year’s pumpkin (Halloween 2014):  NASPGHAN Postgraduate Course 2014 -Liver Module – gutsandgrow

This year’s pumpkin:

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Why the Genetics of Inflammatory Bowel Diseases Matter Now

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A terrific update on the genetics of inflammatory bowel diseases (DPB McGovern, S Kugathasan, JH Cho. Gastroenterol 2015; 149: 1163-76) explains why and how this information matters right now.  The article is a little difficult to read due to its review of highly technical material.

Here’s what I think were the key points:

  • Big advances in understanding the genetics started with the first genome-wide association studies (GWAS) using genome-wide single nucleotide polymorphisms (SNP) chips in 2005.  “The conceptual basis of GWAS is that most complex (ie, not single-gene Mendelian) genetic disorders are polygenic, being driven by multiple common genetic polymorphisms.”
  • “Early GWAS identified the most significant loci.”  Now, more than 200 loci associated with IBD have been identified with GWAS and Immunochip data. Table 1 lists these loci over 4 pages.  About 2/3rds of these are associated with Crohn’s disease (CD) and ulcerative colitis (UC) whereas the remaining 1/3rd are unique to either CD or UC.
  • These loci provide insight into disease mechanisms. NOD2 mutations result in “impaired activation of NF-κB” This supported “the general concept that deficiencies of innate immune cell function represent a central factor in Crohn’s disease, distinguishing it from ulcerative colitis.”
  • ATG16L1 gene mutation “establish the fact that the CD risk allele is correlated with impaired autophagy.”  This is leading directly into treatment efforts.
  • IL23R.  “The most significant association is Arg381Gln…confers a 2- to 3-fold protection against development of IBD.”  The protective effect is thought to be due to “decreased numbers of interleukin (IL)-23 dependent CD4+ Th17 and CD8+ Tc17 cells…decreasing IL-23 signaling, such as through monoclonal antibody blockade of anti-p40 or anit-p19 may be beneficial.”
  • FUT2 mutations.  These mutations affect the mucus layer in Crohn’s disease.
  • Studies in non-Caucasians highlight other susceptibility regions.
  • “Currently, sequencing of the whole exome has become not only a practical method but also a cost-effective option to identify functionally relevant variants in the protein encoding regions of the genome.”

Very Early Onset IBD:

  • Whole exome sequencing (WES) identified XIAP (X-linked inhibitor of apoptosis) in a case of boy with very early onset (VEO) IBD.  XIAP is a positive regulator of NOD2 function.  WES has also identified FOXP3, and IL10RB genes.
  • “The VEO group experiences a more severe disease course and more frequently shows a positive family history for IBD in support of higher genetic load.”  Table 2 lists ~40 genes associated with VEO.  These genes are involved in epithelial barrier function, neutropenia/defects in phagocyte function, hype-and autoinflammation, and  regulatory T cells and immune regulation.

Genetic Testing Will Impact Current Therapies and Help Explain Extraintestinal Manifestations:

  • Currently testing for TPMT variations is recommended prior to use of thiopurines due to concerns of toxicity in individuals with decreased metabolism of these medications.  However, genetic testing can identify other individuals with propensity to leukopenia (eg. NUDT15 polymorphism) and those with increase risk for pancreatitis (eg. HAL-DQA1-HLA-DRB1)
  • Primary Sclerosing Cholangitis (PSC) is associated with numerous genetic loci as well. PSC “genetically is more similar to UC than to CD.” Most other extraintestinal manifestation studies have been underpowered.
  • IBD share more genetic similarity to spondyloarthropathy (SpA) than any other immune-mediated diseases.  “The vast majority of shared susceptibility loci are concordant between IBD and SpA.”
  • With regard to psoriasis, the genetic relationship to IBD is complex.  Anti-TNF agents can cause psoriaform lesions in IBD patients.  In addition, anti-IL17a therapy, “so successful in psoriasis, appears to worsen Crohn’s disease” but not in those with a TNFSF15 variant.  Specific genotyping may help identify which patients with CD are susceptible to psoriaform lesions and those who may improve with therapy typically given for psoriasis.

My take: This article shows how understanding genetics of IBD is providing insight into pathophysiology and more personalized treatment approaches.

Briefly noted: EM Stoffel, CR Boland. Gastroenterol 2015; 149: 1191-1203. Excellent review of the genetics and genetic testing for Hereditary Colorectal Cancer.  The review includes polyposis syndromes and Lynch syndrome.

Atlanta Botanical Gardens

Atlanta Botanical Gardens