Medical Progress: Toward Hepatitis C Elimination

JE Squires, WF Balistreri. J Pediatr 2020; 221: 12-22. Full text: Treatment of Hepatitis C: A New Paradigm toward Viral Eradication

This is a terrific article describing the improvements in treatment and challenges ahead for hepatitis C infection.

The authors note that widespread treatment has led to recommendations that primary health providers manage treatment in most adults.  Given the safety and effectiveness of these newer agents, the authors propose a similar algorithm for children (Figure 3).

The authors note the following:

“Just as has occurred in adults, the rate of discovery related to pediatric HCV therapy is outpacing traditional publication methods and many recommendations are no sooner published than they are “outdated” as newer data re-shapes the therapeutic landscape. To combat this challenge, the AASLD and IDSA have partnered to create an updated web experience resource to facilitate rapid access to treatment information (https://www.hcvguidelines.org/). A section of this document is dedicated to children, however, as of this writing, a similar comprehensive ‘living’ document is not available for pediatric populations, thus, care teams should be cognizant of the most current published data and increase their awareness of upcoming studies and DAA’s ‘in the pipeline’ that may soon be available.”

My take (borrowed from authors):

  • “Every child deserves equitable access to a cure for HCV.”
  • “Progress toward elimination of HCV infection in the US is at hand; however, both community/primary care practices and federal commitment will be required.”
  • “The role of the primary care practitioner will be enhanced [and needs to be incentivized]. It is likely that the new paradigm will be to screen and to initiate DAA treatment in patients with HCV infection.”
  • “Consultation with a hepatologist/infectious disease specialist would, thus, be reserved for selected patients (nonresponsive or those with advanced fibrosis).”

Related blog posts:

Great Issue: We Need More Negative Studies (Published)

A recent ACG “Negative Issue” had some terrific articles –thanks to Ben Gold for sharing his issue.

Here are a few of the studies:

  1. Buspirone had similar efficacy as placebo in a randomized clinical trial for childhood functional abdominal pain, (n=117)  Full text: Comparison of the Efficacy of Buspirone and Placebo in Childhood Functional Abdominal Pain Key finding: Treatment response rates for buspirone and placebo were 58.3% and 59.6% at week 4 (P = 0.902) and 68.1% and 71.1% at week 12 (P = 0.753), respectively.
  2. IBS does not increase mortality in a nationwide cohort study (>300,000 in study)  Full text: Mortality Risk in Irritable Bowel Syndrome Key finding: After adjustment for confounders, IBS was not linked to mortality (HR = 0.96; 95% CI = 0.92–1.00) …and patients with IBS not undergoing a colorectal biopsy were at no increased risk of death (HR = 1.02; 95% CI = 0.99–1.06).
  3. Mongerson was not effective for active Crohn’s disease in a large phase 3 study, n=701 Full text: Mongersen (GED-0301) for Active Crohn’s Disease Key finding: The primary endpoint, clinical remission achievement (CD Activity Index score <150) at week 12, was attained in 22.8% of patients on GED-0301 vs 25% on placebo (P = 0.6210). At study termination, proportions of patients achieving clinical remission at week 52 were similar among individual GED-0301 groups and placebo.
  4. Treatment of H pylori did not increase the risk of C difficile infection (retrospective study)  Full text: Treatment of Helicobacter pylori & Clostridium difficile  Key finding: Of these 38,535 patients with H pylori based on endoscopic pathology, urea breath testing, or stool antigen, 284 (0.74%) had subsequent CDI. Those who developed CDI were less likely to have received treatment for HP within the VHA (66.2% vs 74.8%, P < 0.001)
  5. Percutaneous liver biospy was not safer when done by experienced clinician compared to a fellow, n=212 biopsies  Full text: Major Complications of Pediatric Percutaneous Liver Biopsy Do Not Differ Among Physicians With Different Degrees of Training  Key finding: No significant differences were found between groups (fellows vs staff) regarding number of punctures (median of 1.7 for both), nonrepresentative biopsies (4.2% vs 2.6%), and hemoglobin drop (median of 0.7 vs 0.5 g/L).  Interestingly, in the discussion, the authors assert: “previous studies do not support the conclusion that ultrasound-guided biopsies are superior in terms of safety or adequacy when compared with the use of ultrasound to mark the puncture” (this is based on a study referenced from 2007:  J Gastroenterol Hepatol 2007;22(9):1490–3.)  However, given that severe complications from liver biopsy are infrequent, this current study may be underpowered to detect a small difference between experienced clinicians and fellows.

Related blog posts:


It’s come to this:  Link: YouTube: Dirty Dancing Remake -Safest with a Lamp (this link is for Bernsie). 4 minute video.

High Survival Rates for Biliary Atresia Patients Needing Liver Transplantation

A recent retrospective study (SA Taylor et al. J Pediatr 2020; 219; 89-97) examined patients enrolled in the Society of Pediatric Liver Transplantation (SPLIT) registry, including 547 before 2002 and 1477 after 2002.

Key findings:

  • Before 2002, patient and graft survival were 81% and 90%.
  • After 2002, patient and graft survival were 90% and 97%. This improvement is perhaps more impressive as there was evidence of increased disease severity at time of transplantation in the later cohort.
  • The reasons for these improved outcomes include reduced relisting for transplant, less rejection, less culture-proven infection, fewer reoperations, and less vascular complications (eg. hepatic artery thrombosis and portal vein thrombosis).
  • Donor age (0-5 months) was a risk factor for graft loss; compared to 1-17 years, the hazard ratio was 5.525.  However, in the later group, recipient age of ≤11 months was no longer a risk factor for patient death.
  • Bacterial infection or sepsis remain the leading cause of death after transplantation.

Due to improvement in survival, the authors note that some have advocated for primary liver transplantation instead of Kasai portoenterostomy.  “A report of 626 patients with biliary atresia, of whom 50% underwent primary liver transplantation without Kasai portoenterostomy, demonstrated improved survival.” (JAMA Surg 2019; 154: 26-32)

My take: This information about survival is certainly encouraging –though many challenges remain, especially to improve comorbidities.

Related blog posts:

Island Ford Nat’l Recreational Area, Sandy Springs

Alpha-1-Antitrypsin Deficiency

A recent terrific review on Alpha-1-Antitrypsin (A1AT) Deficiency: P Strnad et al. NEJM 2020; 382: 1443-55

Background:

  • 95% of A1AT deficiency is due to homozygosity for the Z allele; prevalence of 1 in 2000 in those of European descent.
  • A1AT protects the lung tissue against attack by the enzyme neutrophil elastase.
  • The presence of A1AT genetic variants suggests that these mutations may confer a selective advantage, perhaps by amplifying the inflammatory response to invasive respiratory/gastrointestinal infections.

Pathophysiology/Clinical Features:

  • Table 1 lists the key alleles/mutations associated with A1AT deficiency -17 deficiency/null listed including: F, I, Iners, King’s, M-malton, M-procida, Pittsburgh, Queen’s, S, S-iyama, Z, QO-bellingham, QO-granitefalls, QO-hongkong
  • S allele deficiency often results in disease (emphysema, cirrhosis) in the setting of SZ heterozygotes.  The disease is typically less severe than in ZZ disease.  This allele is the most common deficiency variant (1 in 5 in Southern Europe, 1 in 30 in U.S.)
  • Z allele deficiency is the most common severe deficiency variant.  Carrier frequency: 1 in 27 persons in Northern Europe, 1 in 83 in the U.S. It is NOT seen in China, Japan, Korea, Malaysia, or Northern and Western Africa.

PI ZZ Genotype:

  • 73% of infants with PI ZZ genotype had elevated ALT level in the 1st 12 months of life
  • Cholestatic jaundice noted in 10% of infant; 15% of these infants progress to juvenile cirrhosis
  • Only 15% with abnormal ALT values by 12 years of age
  • 35% of adults with ZZ genotype show clinically-significant liver fibrosis. Risk factors for advanced fibrosis: male gender, metabolic syndrome/obesity, and alcohol consumption.

Lung Disease Due to A1AT Deficiency:

  • The clinical features of lung disease due to A1AT deficiency are “mainly indistinguishable from those of nonhereditary emphysema…this is partly why severe A1AT deficiency remains undiagnosed in approximately 90% of case, with an interval of 5 to 7 years from the onset of symptoms to diagnosis.”  When the diagnosis is late, lung disease has become irreversible.
  • Early diagnosis allows lifestyle changes (eg. smoking cessation), reduction in occupational risks, and access to therapies.

MZ Phenotype:

PI MZ genotype is more susceptible to multiple disorders, including a predisposition to COPD (at least among smokers) with odds ratio of 1.4.  Other conditions with increased risk: NAFLD-related cirrhosis (OR 3-7), Alcoholic cirrhosis, and CF-associated liver disease

Treatment:

  • Smoking cessation
  • Plasma-purified A1AT infusions.  “Randomized, controlled trials have focused on decreased loss of lung density as the primary efficacy outcome;” however, augmentation therapy has not been to shown to effect other measures, “such as FEV1, quality of life, or exacerbation of COPD.”

Related blog posts:

Also, this study was previously alluded to by this blog, but now is in print:

Briefly noted: X Lu et al. SARS-CoV-2 Infection in Children (NEJM 2020; 382: 1663-5). In 171 Chinese children with confirmed SARS-CoV-2 infection, 41.5% had fever during illness; 27 (15.8%) had no symptoms of infection or radiographic findings. Three required ICU/ventilator support; all had coexisting conditions.  One 10 month old child with intussusception died.

Stratifying Cystic Fibrosis Liver Disease with Ultrasonography

A recent multicenter case-controlled study (MJ Siegel, J Freeman, W Ye et al. J Pediatr 2020; 219: 62-9) show that ultrasonography can identify children with cystic fibrosis (CF) at increased risk for developing advanced CF liver disease; it is well-recognized that currently advanced CF liver disease occurs predominantly in children.

Among 722 participants who underwent ultrasonography as part of a planned 9 year research study, 65 had heterogeneous liver pattern and 592 had a normal liver pattern at baseline.

Key findings at planned 4-year interim analysis in a subgroup of 55 with (baseline) heterogeneous liver pattern and 116 with (baseline) normal liver pattern:

  • Those with heterogeneous liver pattern had higher median biochemical markers of liver disease: ALT 42 vs 32, GGT 36 vs 15, AST to platelet ratio index: 0.7 vs 0.4
  • Those with heterogeneous liver pattern were at ~9-fold increased risk of developing a nodular liver pattern (23% vs. 2.6%).
  • The authors did not identify specific clinical risk factors that predict the development of nodular liver ultrasound pattern

My take: Even among those with a heterogeneous pattern, the majority will not develop a ultrasonography (nodular) pattern of advanced liver disease.  Much more insight in this area is needed with the advancement in medical treatments and with the more availability of elastography.

Related blog posts:

Island Ford Nat’l Recreation Area/Chattahoochee River

Elevated Bilirubin in Newborns with Down Syndrome

Elevated bilirubin in newborns with Down syndrome has been previously reported but the frequency has not been well-described.  A recent retrospective report (TM Bahr J Pediatr 2020; 219; 140-5) compared 357 neonates with Down syndrome to 377,368 controls.

Key findings:

  • Compared with control subjects, neonates with Down syndrome had 4.7 times the risk of having an initial total serum bilirubin exceeding the 95th percentile (23.5% vs 5.0%), 8.9 times the need for phototherapy (62.2% vs 7.0%) and 3.6 times the readmission rate for jaundice (17.4 vs 4.8 per 1000 live births).

The authors note that the basis for the increased risk of hyperbilirubinemia may be early hemolysis related to “neocytolysis” which is due to destruction of RBCs following a change from low to high oxygen exposure. Other factors could include slower bilirubin conjugation/elimination and poor feeding.

My take: This study indicates that infants with Down syndrome have a substantial risk of hyperbilirubinemia.  And, while you are checking a bilirubin, it is worthwhile to obtain a direct bilirubin as cholestasis is increased in infants with Down syndrome too; the latter is often transient and/or associated with other organ involvement.

Related blog post: Neonatal cholestasis and Down syndrome

Island Ford Nat’l Recreation Area/Chattahoochee River, Sandy Springs

Autoimmune Hepatitis Outcomes, Grand Rounds on Splenomegaly, Hydroxychloroquine for SARS-CoV-2 & Zantac Warning

Here’s a commentary explaining why hydroxychloroquine is NOT proven effective:

Annals of Internal Medicine -Link: A Rush to Judgment? Rapid Reporting and Dissemination of Results and Its Consequences Regarding the Use of Hydroxychloroquine for COVID-19

Some of the key points:

  • While the study suggested more rapid clearance of SARS-CoV-2 virus at day 6 in those treated with hydroxychloroquine/azathioprine (n=20), the authors excluded 6 from the treatment group including one patient who died and three who were transferrred to the ICU.  In addition, the treatment group had a lower viral load at the start of treatment.
  • Other viral infections, including influenza, have also had in vitro data suggesting efficacy with hydroxychloroquine but this did not translate into clinical efficacy in clinical trials.
  • “The hydroxychloroquine shortage not only will limit availability to patients with COVID-19 if efficacy is truly established but also represents a real risk to patients with rheumatic diseases who depend on HCQ for their survival.”

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A Di Giorgio et al (J Pediatr 2020; 218: 121-9) provide long-term data (median f/u of 14.5 years) from a retrospective review on 83 children with autoimmune hepatitis (AIH, n=54)/autoimmune sclerosing cholangitis (ASC, n=29). Median age at presentation, between 2000-2004 was 12.1 years

Key findings:

  • 29% had histologic evidence of cirrhosis at diagnosis
  • At a median followup of 14.5 years, 99% were alive, 11 underwent transplantation.  In those who underwent transplantation, 5-year and 10-year survival was 95% and 88% respectively.
  • ASC was associated with IBD in 73% of cases, compared to 33% of AIH patients.
  • Treatment: 95% of all patients had normalization with transaminases with immunosuppressive treatment (most commonly azathioprine with prednisone 2.5-5 mg/day). ASC patients also received ursodeoxycholic acid 15-20 mg/kg/day.
  • Immunologic remission: 47% achieved immunologic remission which required normal IgG levels and negative/low ANA/SMA <1:20 in addition to normal transaminases.
  • Liver transplantation was needed in 28% of ASC compared to 9% of AIH patients; overall, 83% experienced 15-year transplant-free survival. Median age of those needing a liver transplant was 19.3 years.
  • Immunosuppression withdrawal was attempted in 12 patients after a median of 4.5 years of treatment.  9 were able to stay off immunosuppression.
  • An increase in case frequency was noted during the last 4 decades at this center, from 3.6 cases/year to 5.4 case/year.
  • Four patients had isolated infrequent autoantibodies of anti-SLA (n=3) nad antiLC-1 (n=1). SLA =liver soluble antigen, LC-1 =liver cytosol antibody type 1.  Thus, in those with suspected AIH/ASC, testing for these autoantibodies is important in ~5%.
  • Pathology: 18% did not have classical features of interface hepatitis.  Instead, some had lymphocytic/lymphoplasmocytic infiltrate without spillover into the parenchyma.
  • Progression from AIH to ASC occurred in 3 patients on followup cholangiography.
  • ASC would have been overlooked in 41% if one relied on pathology alone -reaffirming need for biliary imaging.

My take: This article has a number of useful points and with an overarching message that long-term outcomes are good for children with AIH/ASC.

Related blog posts:

B Freiberg et al. 2020; 218: 221-31. This grand rounds describes the extensive workup of a 12 year old with splenomegaly ultimately due to splenic vein stenosis.  The report provides a nice review of hepatologic, hematologic, infectious, and other causes of splenomegaly as well as a work-up algorithm. (look for everything).

Initial evaluation per algorithm should start with CBC/d, retic, blood smear, liver biochemistries, GGT, coags, EBV VCA IgM, CMV IgM, Parvovirus IgM, and complete abdominal ultrasound with doppler.

Hepatologic causes of splenomegaly include the following:

  • cirrhosis with portal hypertension
  • autoimmune hepatitis/autoimmune sclerosing cholangitis
  • congenital hepatic fibrosis
  • hepatoportal sclerosis
  • nodular regenerative hyperplasia
  • storage disease and inborn errors of metabolism which includes lipidosis (Gaucher, Niemann-Pick), mucopolysaccharidoses, defects in carbohydrate metabolism (galactosemis, hereditary fructose intolerance), sea-blue histiocyte syndrome
  • anatomic disorders: portal/splenic thrombosis, Budd-Chiari, cysts, hamartomas, hemangiomas, hematoma, peliosis

Other causes of splenomegaly: infecions, hematologic-oncologic, and rheumatic disorders

Related blog posts:

The U.S. Food and Drug Administration today announced it is requesting manufacturers withdraw all prescription and over-the-counter (OTC) ranitidine drugs from the market immediately. This is the latest step in an ongoing investigation of a contaminant known as N-Nitrosodimethylamine (NDMA) in ranitidine medications (commonly known by the brand name Zantac). The agency has determined that the impurity in some ranitidine products increases over time and when stored at higher than room temperatures and may result in consumer exposure to unacceptable levels of this impurity. As a result of this immediate market withdrawal request, ranitidine products will not be available for new or existing prescriptions or OTC use in the U.S.

New FDA testing and evaluation prompted by information from third-party laboratories confirmed that NDMA levels increase in ranitidine even under normal storage conditions, and NDMA has been found to increase significantly in samples stored at higher temperatures, including temperatures the product may be exposed to during distribution and handling by consumers. The testing also showed that the older a ranitidine product is, or the longer the length of time since it was manufactured, the greater the level of NDMA. These conditions may raise the level of NDMA in the ranitidine product above the acceptable daily intake limit.

Liver Shorts March 2020 & COVID-19 Screenshots

Sofusbuvir and Ribavirin for children with hepatitis C infection (3-12 yrs, genotype 2 or 3) P Rosenthal et al. Hepatology 2020; 71: 31-43. n=54.  SVR12 was 98% (one patient did not complete treatment).

Alpha-one antitrypsin heterozygositiy contributes to cirrhosis in fatty liver disease. Liver Transplantation 2020; 26: 17-24. From the discussion: “unexpected PASD+ globules, in the context of advanced liver disease, are a specific finding that indicates the presence of a mutant A1AT allele.”  Of 196 explanted livers from NASH patients, 21 (11%) has PASD+ globules; however, among NASH patients the frequency was 47%.  Also, the Z allele was present in 10% of all tested liver explants, this exceeds the 2% rate in the general population.  Thus, in agreement with other studies, A1AT heterozygosity contributes to chronic liver failure, but may affect fatty liver disease more than other chronic liver diseases.

Durability of HBsAg Loss in Hepatitis B AS Alawad et al. Clin Gastroenterol Hepatol 2020;18: 700-09.  In this retorspective study form NIH, 89/787 HBsAg-positive patients cleared HBsA; 65 had confirmed clearance. (spontaneous in 19, post-interferon in 22, and post-NA treatment in 24). 62 of 65 remained negative after a mean time of 9.6 years. 3 patients had seroreversion at a mean of 20 months after stopping therapy, though this was transient in 2 of 3 and may have been a false-positive.

Are Medications Contributing to Obesity and Fatty Liver Disease? ~25% of U.S. adults take a prescription medication  that often produces obesity as an adverse effect. (Hales CM et al. Obesity Week 2019, Link to Abstract T-OR-2037). PRESCRIPTION MEDICATIONS THAT PROMOTE WEIGHT GAIN: Prevalence of Use Among U.S. Adults, 2013-2016 Common obesogenic medications in this cohort, (n=11,055), included all glucocorticoids, beta-blockers, and antihistamines and some agents among antidepressants, antipsychotics, antidiabetics and progestin-only contraceptives.  Medications were defined as promoting weight gain according to the Endocrine Society Clinical Practice Guideline for the Pharmacological Management of Obesity (J Clin Endocrinol Metab, 2015).

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If you have not seen this on YouTube, highly recommend this virtual choir link: Rodean School -Hallelujah


More fallout from Coronavirus: NY Times: Coronavirus May Add Billions to Nation’s Health Care Bill Insurance premiums could spike as much as 40 percent next year, a new analysis warns, as employers and insurers confront the projected tens of billions of dollars in additional costs of treating coronavirus patients.

Topical (& Tasty) Tweets:

Projected 20-Year and 30-Year Survival Rates for Pediatric Liver Transplant Recipients (U.S.)

A recent study (MG Bowring et al. JPGN 2020; 70: 356-63) provides data on pediatric liver transplantation (LT) survival rates and projected survival rates.

This retrospective cohort study included 13,442 first-time pediatric (<18) LT recipients from 1987-2018.

Key findings:

  • Projected 20-year survival rate for pediatric LT from 2007-18: 84.0%
  • Prior 20-year survival rates: 72.8% (1997-2006 cohort) and 63.6% (1987-1996 cohort)
  • Projected 30-year survival rates for pediatric LT from 2007-18: 80.1%
  • Prior 30-year survival rates: 68.6% (1997-2006 cohort) and 57.5% (1987-1996 cohort)
  • Projected outcomes with split LT (28% of 2007-2018 cohort) are similar to outcomes with whole LT

My take: While projections can overestimate and underestimate survival rates, the clear trend has been a remarkable improvement in long-term outcomes.  This published data can provide current expectations when counseling families, though with ongoing improvements in management/development of tolerance, the hope is for even better outcomes.

Related blog posts:

View from the top of Blood Mountain, Ga

“Crushing it:” Practice Guidance for Hepatitis C

Today’s post on Hepatitis C follows a few screenshots from twitter regarding the coronavirus epidemic.

Pediatric report of coronavirus in children: NEJM Full link: SARS-CoV-2 Infection in Children A recent review of 72,314 cases by the Chinese Center for Disease Control and Prevention showed that less than 1% of the cases were in children younger than 10 years of age (n=171)…3 patients required intensive care support and invasive mechanical ventilation; all had coexisting conditions. There was one death in a 10-month-old child with intussusception had multiorgan failure and died 4 weeks after admission.

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As noted yesterday, this post will review a recent practice guidance for hepatitis C

Some specific recommendations for children:

Testing:

  • “All children born to HCV-infected women should be tested for HCV infection. Testing is recommended using an antibody-based test at or after 18 months of age.”
  • “Testing with an HCV-RNA assay can be considered in the first year of life, but the optimal timing of such testing is unknown” (but can be done as early as 2 months of life).
  • “The siblings of children with vertically-acquired chronic HCV should be tested for HCV infection, if born from the same mother.”

Counseling for parents:

  • “Parents should be informed that hepatitis C is not transmitted by casual contact and, as such, children with HCV infection do not pose a risk to other children and can participate in school, sports, and athletic activities, and engage in all other regular childhood activities without restrictions.”
  • “Parents should be informed that universal precautions should be followed at school and in the home of children with HCV infection. Educate families and children about the risk and routes of HCV transmission, and the techniques for avoiding blood exposure, such as avoiding the sharing of toothbrushes, razors, and nail clippers, and the use of gloves and dilute bleach to clean up blood.”

Treatment:

  • “Direct-acting antiviral (DAA) treatment with an approved regimen is recommended for all children and adolescents with HCV infection aged ≥3 years as they will benefit from antiviral therapy, regardless of disease severity.”
  • Early treatment in childhood is expected to be cost-effective compared to treatment at later ages based on previous studies

This chart provides recommendations for pediatric patients who have not received prior direct-acting antivirals. More information at HCVguidelines.org