Hepatitis C in 2020: NASPGHAN Position Paper

DH Leung et al. JPGN 2020; 71: 407-17.  Full Text: Hepatitis C in 2020: A North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Position Paper

This is a very useful summary and some important recommendations –here are a few:

  • Direct-acting antivirals (DAAs) which …[are] highly effective antiviral agents are now approved for use in children as young as 3 years of age and have demonstrated sustained virologic responses exceeding 90% in most genotypes
  • We recommend treatment be considered and offered to all children with chronic HCV as early as 3 years of age with currently approved and anticipated DAA combination therapies.
  • Currently, the American Academy of Pediatrics recommends anti-HCV antibody screening of children with maternal HCV risk factors at 18 months of age, when detection of passively acquired transplacental immunoglobulin G should have waned … Waiting until 18 months of age or older is, however, frequently unpalatable for parents and physicians concerned about reliable follow-up. Therefore, after the infant is 2 months of age, the AASLD-IDSA HCV Guidance Panel suggests consideration of examining serum HCV RNA by polymerase chain reaction (PCR)
  • Interestingly, in the image below, the authors note that most children are asymptomatic; however, the figure suggests the possibility of thyroid disease.  In the text of the article: ” Extrahepatic manifestations of chronic hepatitis C, including membranoproliferative glomerulonephritis, thyroid dysfunction with or without thyroid autoimmune disease, and the development of nonorgan specific antibodies, are exceedingly rare

Recommended Resources for Pediatric Gastrointestinal and Liver Providers

Related blog posts:

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition

Liver Shorts -August 2020

V Cardenas et al. JPGN 2020; 71: 197-202.  Incidence and Sequelae of Liver Injury Among Children Treated for Solid Tumors: Analysis of a Large Single-Center Prospective Cohort

  • Of 1136 solid tumor patients, 160 (14%) experienced liver injury, and the overall frequency of DILI was 4%.
  • DILI was the leading identified cause of liver injury (31%), followed by infection (17%), metastatic/malignant biliary disease (13%), and perioperative liver injury (13%).
  • Most DILI cases (>90%) were mild acute hepatocellular injury episodes that did not result in modification to the chemotherapy plan, and all DILI eventually resolved.

N Kapila et al. Hepatology 2020; 72: 32-41. Full Text Link: Hepatitis C Virus NAT‐Positive Solid Organ Allografts Transplanted Into Hepatitis C Virus–Negative Recipients: A Real‐World Experience

Background: As of April 1, 2019, an estimated 103,000 kidney, 13,500 liver, and 3,800 heart transplant (HT) candidates are awaiting transplantation

Key findings:

  • Seventy‐seven patients who were HCV negative underwent solid organ transplantation from a donor who was HCV viremic. Only one has been a HCV-treatment nonresponder (though several have not completed SVR12).
  • “Our study is the largest to describe a real‐world experience of the transplantation of HCV‐viremic organs into recipients who are aviremic. In carefully selected patients, the use of HCV‐viremic grafts in the DAA era appears to be efficacious and well tolerated.”

M Martinello et al. Hepatology 2020; 72: 7-18Short‐Duration Pan‐Genotypic Therapy With Glecaprevir/Pibrentasvir for 6 Weeks Among People With Recent Hepatitis C Viral Infection

  • This was an  open‐label, single‐arm, multicenter, international pilot study; adults with recent HCV (duration of infection < 12 months) received glecaprevir/pibrentasvir 300/120 mg daily for 6 weeks.
  • At baseline, median estimated duration of infection was 29 weeks (range 13, 52) and median HCV RNA was 6.2 log10 IU/mL (range 0.9, 7.7). SVR12 in the intention‐to‐treat and per‐protocol populations was achieved in 90% (27/30) and 96% (27/28), respectively.

H Verkade et al. JPGN 2020; 71: 176-83. Systematic Review and Meta-analysis: Partial External Biliary Diversion in Progressive Familial Intrahepatic Cholestasis

  • With regard to  pruritus improvement, 104/155 (67%) were responders, 14/155 (9%) had partial response, and 37/155 (24%) were nonresponders.

K Patel et al. Hepatology 2020; 72: 58-71. Cilofexor, a Nonsteroidal FXR Agonist, in Patients With Noncirrhotic NASH: A Phase 2 Randomized Controlled Trial

  • “Cilofexor for 24 weeks was well‐tolerated and provided significant reductions in hepatic steatosis, liver biochemistry, and serum bile acids in patients with NASH.”

NOT Screening At-Risk Infants for Hepatitis C

A recent study (S Lopata et al. Pediatrics 2020; 145: e20192482. Link to Abstract/Video: Hepatitis C Testing Among Perinatally Exposed Infants) was well-summarized in a recent practical gastroenterology issue: Full link: Hepatitis C Screening of Infants

An excerpt:

  • During the study period, 384,837 mother-infant dyads were enrolled in the Tennessee Medicaid program, and 4072 of these mothers had HCV during pregnancy…
  • The prevalence of infants with exposure to HCV increased significantly throughout the study with 5.1 infants exposed to HCV per 1000 live births in 2005 and 22.7 infants exposed to HCV per 1000 live births in 2015 with 92.9% of the mothers of these children being white.
  • Only 946 infants (23%) exposed to HCV had HCV testing in the first 2 years of life, and 354 of these infants (41%) had testing per recommended national guidelines…
  • Infants who were exposed to HCV and who were African American or who lived in rural areas next to metropolitan areas were significantly less likely to have HCV testing.

My take: As with adults, this study shows that selective HCV testing is a messy proposition.  This study shows that more than 75% of at risk infants are not being tested for HCV.  Now that curative treatment is available, more needs to be done to address this public health failure.

Online Aspen Webinar (Part 4) -How to Treat Hepatitis C in Children

Below I’ve included a few slides and some notes; my notes may have errors of omission or transcription.

How I Treat Children with Hepatitis C  William Balistreri

Key points:

  • The recommendations for pediatric hepatitis C infection have been rapidly-changing due to a large number of recent studies/new direct-acting antivirals.  There are many new treatment options (see HCVguidelines.org); currently available treatment regimens noted below
  • All children >3 years of age with HCV should be treated –high cure rates (91-100% SVR) and this leads to long-term improvements in health outcomes
  • Test for Hepatitis B before instituting DAA therapy
  • Universal screening has been recommended for all adults >18 years.  This omits the pediatric age group; however, if all pregnant women are screened, the majority of pediatric HCV infections could be identified

Related blog posts:

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:

“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.

——-

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

Liver Briefs -July 2019

NH Ebel et al. JPGN 2019; 68: 788-92Hepatic venous pressure gradient (HVPG) did not correlate with the risk of complications from portal hypertension in this pediatric cohort (n=41); this is in contrast to studies in adults showing the utility of HVPG measurements.

AG Singal et al. Gastroenterol 2019; 156: 2149-57. AGA Practice Update on Direct-Acting Antivirals for Hepatitis C and Hepatocellular Carcinoma. There are 12 best practice advice –here are the first three:

  • BEST PRACTICE ADVICE 1: DAA treatment is associated with a reduction in the risk of incident HCC. The relative risk reduction is similar in patients with and without cirrhosis.
  • BEST PRACTICE ADVICE 2: Patients with advanced liver fibrosis (F3) or cirrhosis should receive surveillance imaging before initiating DAA treatment.
  • BEST PRACTICE ADVICE 3: Patients with advanced liver fibrosis (F3) or cirrhosis at the time of DAA treatment represent the highest-risk group for HCC after DAA-induced sustained virologic response. These patients should stay in HCC surveillance

N Hamdane et al. Gastroenterol 2019; 156: 2313-29. This study found that chronic HCV infection induced specific genome-wide-changes in H3K27ac which correlated with expression of mRNAs and proteins.  These epigenetic changes persisted after an SVR to DAAs or interferon-based therapies. These changes could explain some of the reason why HCC remains a risk after successful treatment with DAAs.

DT Dieterich et al. Gastroenteroloy & Hepatology 2019; 15S: 3-11 Link: “A simplified algorithm for the management of Hepatitis C Infection”  An excerpt:

“The algorithm begins with universal HCV screening and diagnosis by testing for HCV antibody with reflex to polymerase chain reaction to detect HCV RNA. The pretreatment evaluation uses platelet-based stratification to initially assess fibrosis, and the pan-genotypic regimens glecaprevir/pibrentasvir or sofosbuvir/velpatasvir are recommended for treatment. Unless clinically indicated, on-treatment monitoring is optional. Confirmation of cure (undetectable HCV RNA 12 weeks posttreatment) is followed by harm-reduction measures, as well as surveillance for hepatocellular carcinoma every 6 months in patients with advanced fibrosis/cirrhosis.”  My take: This algorithm is much simpler than the expanded recommendations from HCVguidelines.org website, though these agents, to my knowledge, do not yet have a pediatric indication.

 

Liver Briefs -June 2019

YH Yeo et al. Hepatology 2019; 69: 1385-97.  The prevalence of high risk individuals in the U.S. who are susceptible (not immune) to hepatitis B has decreased from 83% to 69% from 2003 to 2014.  That still leaves 64 million who would benefit from HBV vaccination.

M Sharma et al. Hepatology 2019; 69: 1657-75. This meta-analysis compared therapies for primary prevention of esophageal varices and concluded that nonselective beta-blocker (NSBB) monotherapy may decrease all-cause mortality and carried a lower risk of serious complications than variceal band ligation (VBL). However, the commentary (1382-84 by L Laine) reaches a different conclusion. “Current recommendations for primary prevention with VBL or NSBB or carvediolo still appear to be acceptable…using a shared decision-making approach” to weigh issue such as daily medication or periodic endoscopy.

J Nguyen et al. J Pediatr 2019; 207: 90-6. This study modeled the cost-effectiveness of early treatment with direct-acting antiviral therapy in adolescents with hepatitis C infection.  With pangenotypic agenst, the cost would be $10000 to $21000 per QALY gained.

S Trinh et al. Clin Gastroenterol Hepatol 2019; 17: 948-56. This retrospective hepatitis B study examined the changes in renal function between 239 tenofovir disoproxil fumarte (TDF) treated patients and 171 entecavir treated patients.  Key finding: TDF was not associated with higher risk of worsening renal function in this cohort with a mean followup of 43-46 months in patients with baseline normal renal function.  In patients with renal impairment, deterioration of renal function was noted in TDF-treated patients.  Thus, TDF should be avoided in patients with impaired renal function.

 

Rhododendrom in Sandy Springs

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Liver Shorts: May 2019

ED Bethea et al. Clin Gastroenterol Hepatol 2019; 17: 739-47. Using a Markov-based mathematical model, the authors “found transplanting HCV-positive livers into HCV-negative patients with preemptive DAA therapy to a cost-effective strategy that could improve health outcomes.”

A Villanueva. NEJM 2019; 1450-62. This is a succinct review of hepatocellular carcinoma (HCC). Some points:

  • More than 1 million patients will die from liver cancer in 2030.
  • The rate of death from liver cancer increased 43% from 2000 to 2016,.  The 5-year survival rate is grim at only 18%.  Only pancreatic cancer is more lethal.
  • HCC is rare among patients without preexisting liver disease.  Cirrhosis is the main risk factor, though hepatitis B has direct oncologic effects even in the absence of cirrhosis.
  • The authors note that cancer surveillance has no “high-quality randomized controlled trials.” However, this may be due to difficulties with enrollment. In one study, 99%of patients declined to assume the risk of being randomly assigned to the nonsurveillance group. Nonetheless, mathematical models, and lower quality studies all show survival benefits of surveillance.

Related blog post:

  • Liver Shorts April 2019 Obesity/NAFLD and alcoholic liver disease are driving an increase in HCC and liver cancer mortality

Expanding Organ Transplantation with Hepatitis C-Positive Donors

A recent study (AE Woolley et al NEJM 2019; 380: 1606-17) highlighted the outcomes of heart and lung transplant (uninfected) recipients of organs from HCV-infected donors (“DONATE HCV” trial).

In this study, 44 patients (36 lung transplant recipients, 8 heart transplant recipients) were treated preemptively with 4 weeks of sofosbuvir-velpatasvir to block viral replication.

Key findings:

  • 42 of 44 (95%) had a detectable viral load immediately after transplantation.
  • The first 35 (who have all completed 6 months of folllowup) all cleared HCV viremia –undetectable HCV at 6 months post-transplantation
  • No treatment-related complications were noted

In the associated editorial by EA Blumberg (1669-70), it is noted that organs for transplantation are in short supply for the more than 113,000 persons on waiting lists in the U.S.  “In 2018, only 36,500 persons received transplants…and 12,225 persons were removed from the waiting list because of death or progressive illness than rendered them” too sick for transplantation.

HCV donors will expand the donor pool substantially (up to one-third more donors) and these donors are typically younger and with fewer coexisting conditions.

My take: With the high response rate of the newer direct-acting antivirals (100% in this study) along with the (cost) effectiveness of a shorter course, this study shows how promising HCV-positive donors are for improving outcomes in patients in need of organ transplantation.  Long term data are still needed to determine if there are unforeseen problems (eg. late severe relapse of HCV, increased cardiovascular disease).

Related blog post: Increased Organ Availability Related to Opioid Epidemic