Methods: The authors would utilize livers from donors with hepatitis C if they had a “normal gross appearance or, in cases in which a liver biopsy was indicated, acceptable histology less than grade 2 inflammation and less than stage 2 fibrosis (Batts-Ludwig classification)”
292 patients, 61 rHCV− received DNAT+ livers (study group), and 231 rHCV− received DNAT− (aviremic donors [nuclear acid test‐negative donors]) (2018-2019)
1‐year post‐LT patient and graft survival were similar between groups
In the study group, 4 patients died, and 1 patient required retransplantation within the first year post‐LT (all unrelated to HCV)
51 patients completed DAA treatment, all achieving sustained virologic response for 12 or more weeks (SVR‐12) (one required re-treatment)
Given the limited organ availability, using livers from donors with hepatitis C has the potential to reduce waitlist times and waitlist mortality.
My take: Liver transplantation with hepatitis C has become bidirectional; livers are being received by those with liver failure due to hepatitis C and failed livers are being replaced by donors infected with hepatitis C.
Methods: N=85. Liver stiffness measurement (LSM), by vibration-controlled transient elastography and noninvasive fibrosis scores (Firbosis-4, aspartate aminotransferase-platelet ratio index), were obtained before and 12 months after eradication with ledipasvir-sofosbuvir.
Overall, median baseline LSM was 5.8 (IQR, 4.2-6.5) and at follow-up 5.1 kPa (IQR, 4-6 kPa) (P = .045)
16 patients (19%) experienced regression, and 46 (54%) nonprogression of LSM
The median baseline FIB-4 and aspartate aminotransferase-platelet ratio index scores were 0.34 (IQR, 0.22-0.47) and 0.35 (0.24-0.57), and at follow-up 0.3 (IQR, 0.22-0.34) and 0.2 (0.18-2.8) (P < .001, <.001), respectively
Limitations: In Egypt, HCV genotype 4 is predominant; thus, findings could be different with other HCV genotypes. In addition, the ‘gold’ standard in assessing fibrosis remains a liver biopsy.
In many liver conditions, effective therapy has been associated with histologic improvement/regression. So, while the findings in this study are expected, it is still nice to see more evidence of this outcome.
My take: This study supports the notion that elimination of HCV is associated with either regression or non-progression of liver fibrosis. Treatment prior to extensive liver damage is likely both effective and cost-effective.
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).”