In this study, the authors used a state-transition model to assess cost-effectiveness of hepatitis C virus (HCV) infection in children; the model treated a hypothetical cohort of 10,000 children with chronic HCV at age 6 years with combination therapy of sofosbuvir/ledipasvir for 12 weeks vs deferring treatment until 18 years of age.
The incremental cost effectiveness of early treatment of young children was $12 690 per QALY gained after 20 years, which is considered cost effective compared with deferred treatment.
The authors note that if the cost of DAA medications dropped by 60%, then early treatment would not be more cost effective.
However, early treatment of 10,000 children would prevent 330 cases of cirrhosis, 18 cases of hepatocellular carcinoma, and 48 liver-related deaths.
The investigators presented an additional scenario treating children as young as 3 years of age and using alternative treatment with the pan-genotypic combination of glecaprevir/pibrentasvir for 8 weeks; using glecaprevir/pibrentasvir resulted in an incremental cost effectiveness of $12 563 per QALY compared with deferring treatment to age 18 years.
All cost effective models have built in assumptions. This model, for example, presumes each patient is offered treatment only once and does not get reinfected before age 18 years.
Other aspects about early treatment that are difficult to quantitate:
Improved adherence at younger age which improves cost effectiveness
Reduction in transmission of HCV as a consequence of successful treatment
Detrimental effects of untreated/deferred treatment HCV on quality of life, psychosocial health, and cognitive functioning
My take: This study (& editorial) demonstrate that early treatment of HCV is a good value and delivers non-economic benefits as well. Every child (>3 years) with HCV should be treated and cured of HCV infection.
“We pooled data from 8 phase 2 or phase 3 trials of treatment-naïve patients with HCV genotype 1 to 6 infections, without cirrhosis or with compensated cirrhosis, who received 8 weeks of glecaprevir/pibrentasvir.” (n=1248) Key finding: Overall rates of sustained virologic response at post-treatment week 12 were 97.6% (1218 of 1248) in the intention to treat (ITT) and 99.3% (1218 of 1226) in the modified ITT populations.
This review discussed the use of SMOFlipid that includes soybean, medium-chain triglycerides, olive and fish oils. Key points:
“Lipid minimization strategies have also been shown to reverse IFALD [intestinal failure associated liver disease]. There are, however, considerable concerns regarding adequate weight gain, compromise to neurodevelopment, and EFAD [essential fatty acid deficiency]”
“Thee is actually considerable safety data for CLE [composite lipid emulsion] in neonates, albeit over the short term.”
“In Canada, CLE is currently the lipid emulsion of choice for all infants at risk of IFLAD.”
Methods: “We collected information on weight-adjusted, submaximal physical work capacity (PWC), ultrasound-determined hepatic steatosis, iron indices, and hematologic and metabolic parameters from 390 female and 458 male participants of the Raine Study—a longitudinal study of disease development … in Western Australia”
Key finding: “Fourteen percent of the cohort had NAFLD. PWC was significantly reduced in adolescents with NAFLD compared to adolescents without NAFLD (reduction of 0.17 W/kg, P = .0003, adjusted for sex and body mass index [BMI])… we found NAFLD to be associated with decreased cardiorespiratory fitness, independent of BMI. The relationship between transferrin saturation and PWC in adolescents with NAFLD indicates that functional iron deficiency might contribute to reductions in cardiorespiratory fitness.”
“Thousands of Georgia’s poor and uninsured adults who meet a work or activity requirement will soon be eligible for Medicaid, with perhaps 50,000 added to the rolls within two years…And more than 350,000 very poor, uninsured Georgia adults still won’t meet Georgia’s requirements for Medicaid”
“At the same time, the 400,000 Georgians who bought individual health insurance plans on the federal healthcare.gov Affordable Care Act shopping website will find they can’t do that anymore. Instead they will be directed to contact information for private brokers or insurance companies”
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
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Background: As of April 1, 2019, an estimated 103,000 kidney, 13,500 liver, and 3,800 heart transplant (HT) candidates are awaiting transplantation
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.”
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.
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.
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 CWilliam Balistreri
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
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).”
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 ChildrenA 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
AASLD-IDSA Practice Guidance Panel. Hepatology 2020; 71: 686-721
“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.”
“Direct-acting antiviral (DAA) treatment with anapproved 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
NH Ebel et al. JPGN 2019; 68: 788-92. Hepatic 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.
“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.