CFTR Modulators for Cystic Fibrosis

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Two more studies have shown the effectiveness of CFTR modulators for subsets of patients with cystic fibrosis.

  • JL Taylor-Cousar et al. NEJM 2017; 377: 2013-23
  • SM Rowe et al. NEJM 2017; 377: 2024-35.

In the Taylor-Cousar study, the authors treated patients with homozygous Phe508del cystic fibrosis with either combination tezacaftor-ivacaftor or placebo for 24 weeks. Combination therapy resulted in FEV1 that was 4% higher along with a 35% lower rate of pulmonary exacerbations than placebo.

In the Rowe study which examined patients some retained CFTR function (which occurs ~5% of CF patients), a prospective trial of tezacaftor-ivacaftor had a greater effect on increasing FEV1 than ivacaftor alone.  Ivacaftor monotherapy and tezacaftor-ivacaftor combination therapy were both more effective than placebo.

A related editorial (H Grasemann. pgs: 2085-8) helps provide context to help understand the importance of these studies.  His key point:

“Although CFTR modulator therapies have measurable beneficial effects on some aspects of the disease, there is still an unmet need for truly effective new therapies to be developed for all persons with cystic fibrosis.  The clinical efficacy of the current combination therapies for patients with cystic fibrosis who have the most common CFTR genotype (Phe508del/Phe508del) is suboptimal and falls within the range of established symptomatic therapies, such as nebulized inhaled hypertonic saline or recombinant human DNAse.”

This figure depicts the types of molecular defects: No functional CFTR with framshifts for deletions or insertions (class 1), CFTR trafficking defect due to misfolded protein (class II), defective channel regulation (class III), reduced cholirde conductance (class IV) , reduced synthessis (class V) or decreased CFTR stability (class VI)

Projected Obesity Rates: Majority of Today’s Children Will Be Obese in U.S.

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A recent study (ZJ Ward et al. NEJM 2017; 377: 2145-53) pooled observations from 41,567 children and adults.  They extrapolated this data to created 1000 virtual  populations of 1 million children through the age of 19 years.  They performed simulations to predict future obesity levels.

Key findings:

  • Given current levels of childhood obesity the authors predict 57.3% of today’s children will be obese at the age of 35 years.  They defined obesity for adults as BMI ≥35 and for children as 120% or more of the 95th percentile.
  • For children with severe obesity at age 2 years, approximately 80% will be obese at 35 years; whereas approximately 95% of severely obese 19 year olds will be obese at 35 years of age.
  • About half of the total prevalence of obesity at age 35 years begins in childhood in these models.

Because these are simulations, these projections could be influenced by changing circumstances.  Though, the authors note that these projections have corresponded well to measurable trends thus far in NHANES data.

My take: The increasing rates of obesity projected in these models will have profound effects for health but has implications for a wide range of issues: transportation, housing, social, etc.

South Kaibab Trail, Grand Canyon

Nonalcoholic Steatohepatitis Review

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A concise and useful review of nonalcoholic steatohepatitis (NASH): AM Diehl, C Day. NEJM 2017; 377: 2063-72

A couple points:

  • About 25% of adults have fatty livers in the absence of excessive alcohol consumption
  • NASH is strongly associated with obesity/overweight which occur in  >80% of patients
  • NASH comorbidities in adults: 72% with dyslipidemia, 44% with type 2 diabetes mellitus
  • In a typical patient with NASH, liver fibrosis progresses “at a rate of approximately one stage per decade, suggesting that F2 fibrosis will progress to cirrhosis within 20 years.” However, there is considerable variability.
  • It is expected that NASH will be the leading reason for liver transplantation by 2020.
  • Cirrhosis related to NASH increases the risk of hepatocellular carcinoma with this occuring in 1-2% per year of patients with cirrhosis.
  • NASH is estimated to cost >$100 billion currently in annual direct medical costs
  • Staging of NASH and differentiation from isoloated steatosis identifies those at high risk for sequelae.
  • In Table 2, the authors list more than 10 pharmacologic agents in phase 2/3 studies

Current lifestyle treatment recommendations (for adults):

  • Lose 7% of body weight if overweight or obese
  • Limit consumption of fructose-enriched beverages
  • Limit consumption of alcohol (no more than 1 drink/day for women and 2 drinks/day for men)
  • Drink two or more cups of caffeinated coffee daily

Related blog entries:

 

Panels A & B show typical histologic findings: ballooned hepatocytes (arrows), inflammatory infiltrates (arrowheads), and fibrosis Panel C shows the relative distribution of NASH, cirrhosis, and hepatocellular carcinoma in U.S. Adults.

Research for Fatty Liver Disease

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Recently the AASLD Postgraduate Course discussed emerging treatments for nonalcoholic fatty liver disease/nonalchoholic steatohepatitis. From AASLD News: Emerging Treatments for NASH 

Key point:

  • Quentin Anstee: “It is important to remember that our patients with fatty liver disease will most likely die of cardiovascular disease, not liver disease.”

Four principles in treating nonalcoholic fatty liver disease (NAFLD) to address both cardiovascular and liver risks.

  • Target obesity with lifestyle changes and, possibly, bariatric surgery.
  • Target metabolic syndrome to reduce cardiovascular disease risk using medications with additional liver-directed benefits.
  • Target liver disease to prevent progression of steatohepatitis to fibrosis and cirrhosis.
  • Minimize downstream complications such as hepatocellular carcinoma.

More than 60 phase 3 trials are underway –Primary Therapeutic Targets:

  • PPAR signaling (insulin signaling, glucose and lipid metabolism, energy homeostasis, inflammation)
  • FXR signaling (insulin sensitivity, glucogenesis, lipogenesis)
  • ASK1 signaling (apoptosis)
  • CCR2/CCR5 signaling (inflammation and fibrogenesis).

Low FODMAP –Real World Experience

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HM Staduacher et al. Gastroenterol October 2017; 153: 936–47

Key finding:

  • In this randomized, placebo-controlled study with 104 patients with irritable bowel syndrome (IBS), the researchers spent only 10 minutes per patient teaching the low FODMAPs diet; yet 57% reported adequate relief of symptoms.

AGA Journals blog summary: Can a Diet Low in FODMAP Reduce IBS Symptoms in the Real World?

An excerpt:

Heidi Maria Staudacher et al aimed to investigate the effects of a diet low in FODMAPs compared with a sham diet in patients with IBS, and determine the effects of a probiotic on diet-induced alterations in the microbiota.

They performed a 2×2 factorial trial of 104 patients with IBS. Patients were either given counselling to follow a sham diet or diet low in FODMAPs for 4 weeks, but not the actual foods. Patients also received a placebo or multistrain probiotic formulation, resulting in 4 groups (27 receiving sham diet/placebo, 26 receiving sham diet/probiotic, 24 receiving low-FODMAP diet/placebo, and 27 receiving low-FODMAP diet/probiotic)…

In the per-protocol analysis, a significantly higher proportion of patients on the low-FODMAP diet had adequate symptom relief (61%) than in the sham diet group (39%).

The total mean IBS severity score was significantly lower for patients on the low-FODMAP diet (173 ± 95) than the sham diet (224 ± 89), but there was no significantly difference between patients given probiotic (207 ± 98) or placebo (192 ± 93).

Related blog posts:

 

Liver Articles: Short Takes

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DBE van Wessel et al. JPGN 2017; 65: 370-74.  This retrospective study showed an increase in biliary atresia incidence in preterm infants compared with full-term: 1.06 per 10,000 compared with 0.52/10,000. In addition, 4-year transplant-free survival rates were significantly worse at 21%, whereas 4-year survival rates was 61%. Clearance of jaundice (with Kasai) was achieved in only 23%.

Related post: Biliary Atresia More Common in Preterm Infants

ES Björnsson et al. Clin Gastroenterol Hepatol 2017; 15: 1635-36. This study examined response to steroids in 18 patients with drug-induced autoimmune hepatitis.  Key findings: 14 patients had elevated antinuclear antibodies & there were none with elevated smooth muscle antibodies. Infliximab was most frequent agent (n=11) and nitrofurantoin was other frequent agent (n=3).  Overall, 40% improved after discontinuation of medication, the remainder had prompt responses to corticosteroids.  Relapse did not occur when corticosteroids were discontinued.  Among the infliximab group, there was no evidence of liver injury after transitioning to alternative tumor necrosis factor-α inhibitor.

M Balwani et al. Hepatology 2017; 66: 1314-22. Acute Hepatic Porphyrias -Review. Current recommendations include gene sequencing to confirm all biochemical cases. Biochemical tests are spot urine testing of porphobilinogen (PBG), 5-aminolevulinic acid (ALA), and porphyrins. A normal urine PBG in symptomatic patients “excludes the three most common acute hepatic porphyrias.”  For those with abnormal studies, this reference is a handy.

S Wirth et al. Hepatology 2017; 66: 1102-10.  This study examined the effectiveness of sofosbuvir and weigh-based ribavirin dosing in 12-17 year olds with genotype 2 & 3 Hepatitis C infection.  Duration of treatment was 12 weeks for genotype 2 and 24 weeks for type 3.  Overall, SVR12 was achieved in 51 of 52 (98%); one patient with genotype 3 did not achieve SVR12.

Related post: New HCV Treatment Effective in Adolescents (Genotype 1 study)

F Kanwal et al. Gastroenterol 2017; 153: 996-1005. This study, a retrospective cohort of 22,500 VA patients treated for hepatitis C infection, showed that direct-acting antivirals (DAAs) lowered, but did not eliminate, the risk of hepatocellular carcinoma (HCC). Among the 87% who achieved an SVR, the adjusted hazard ratio for HCC was 0.28.  This was true as well as among patients with cirrhosis.. Hazard ratio for those with compensated cirrhosis was 0.32 compared with 0.18 among those without cirrhosis.

TPN Amino Acid Shortages Following Hurricane Maria

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Thanks to Kipp Ellsworth for this link: FDA Announcement Regarding Medical Product Shortages Related to Puerto Rico Production

An excerpt: the hurricane disrupted Baxter’s amino acids production facilities in Puerto Rico; Baxter is one of the largest manufacturers of this product serving the U.S. market. In order to help mitigate this shortage, the FDA has worked with Baxter to facilitate the temporary importation of amino acids for pediatric and adult formulations of IV amino acids from Baxter facilities in the United Kingdom and Italy. 

When to Check Gastric Residuals in Preterm Infants

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A recent study (A Riskin et al. J Pediatr 2017; 189: 128-34) indicates that routine testing of gastric residual volumes is not needed. In this study of preterm infants ≤34 weeks gestation 239 infants were studied prior and 233 studied after dropping routine checks of gastric residuals.

Key findings:

  • Selective evaluation of gastric residuals was associated with achieving full enteral nutrition 1 day earlier
  • The rate of NEC (stage ≥2) was actually lower in the selective evaluation group (1.7% vs 3.3%) compared to the historic control group

Selective checking of gastric residuals was prompted by the following:

  • abdominal distention
  • vomiting or large regurgitation
  • bilious regurgitation or emesis
  • abnormal behaviors: restlessness, somnolence or apathy
  • increased apnea/bradycardia
  • change in vital signs

While checking gastric residuals had been used to determine feeding intolerance and/or development of necrotizing enterocolitis, this study indicates that routine evaluation is not necessary.

My take: This study challenged a common NICU practice and found that routine assessment of gastric residuals is not needed; selective checking of gastric residuals is sufficient.

12 Year Data: Pros and Cons with Bariatric Surgery

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A recent study (TD Adams et al. NEJM 2017; 377: 1143-55) examines outcomes of bariatric surgery after 12 years.  The ‘skinny’ on this study is that the weight loss/improved metabolic measures associated with bariatric surgery were very durable but there was a small increased risk of suicide among those undergoing bariatric surgery.

In this study, there were three cohorts:

  • Surgery group: 418 patients
  • Nonsurgery group 1: 417 patients. This group had sought surgery but did not receive surgery (often due to insurance coverage)  (147 underwent subsequent surgery)
  • Nonsurgery group 2: 321 patients. This group had not sought surgery (39 underwent subsequent surgery)

Key findings:

  • At 12 yrs, mean change from baseline body weight was -35 kg in surgery group, compared with -2.9 kg in nonsurgery group 1 and 0 kg in nonsurgery group 2
  • Of those with type 2 diabetes in the surgery group, type 2 diabetes remitted in 75% at 2 yrs and remained remitted in 51% at 12 yrs.
  • The surgery group had higher remission rates of hypertension and dyslipidemia as well.
  • 7 deaths by suicide were noted -5 in the surgery group, and 2 in the nonsurgery 1 group but only after the patients had undergone subsequent bariatric surgery

My take: Weight loss and improved metabolic changes at 6 yrs were maintained over the following 6 yrs.  It is troubling that the surgery and/or weight loss is associated with suicide in a small number of patients.

Related blog entries:

Crisis Developing in Blood Supply

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As noted in a previous blog, Business of Blood in Decline, the number of transfusions are declining.  While this is good news, there are a number of worrisome trends that indicate a crisis in the sustainability of the U.S. blood system (HG Klein et al. NEJM 2017; 1485-8).

Some background:

  • U.S. blood collectors draw 35,000 units a day
  • Blood transfusion is ordered in 10-15% of all hospitalizations
  • Less-invasive surgical techniques and other blood-management strategies have reduced demand for blood

So what is the problem?

The U.S. blood supply relies on nonprofit organizations which in turn have relied on blood as a major source of revenue.  With reduction in blood demand and increased screening (e.g. for more infections), the cost per unit has increased; yet, due to stiff competition, there has not been a commiserate increase in reimbursement.

  • 57.1% of America’s Blood Centers in December 2016 reported operating with negative margins
  • 90% of the blood supply is estimated to be provided below cost
  • Due to cost constraints, blood suppliers are less likely to adopt additional measures which could improve patient and donor safety

The authors argue that human blood should not be treated as “just another consumer good.”  Strict economic principles undervalues the need of having a safe, available blood supply. While there have not been clinical consequences thus far, the current model is not sustainable.

My take: The financial market of the blood supply is precarious. This needs to be addressed to ensure the availability of blood when we need it.

Briefly noted -related study: EA Gehrie et al. J Pediatr 2017; 189: 227-31. In this study, the authors tested 220 red blood cell units.  15 (6.8%) had detectable drugs:. opiates, benzodiazepines, stimulants, and barbituates. While none of these units would have been disallowed under current FDA regulations, it is possible that these levels could cause reactions in vulnerable populations, like neonates.  The authors note that allergens, like peanuts and fish, in blood donations can result in anaphylactic transfusion reactions