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therapy is outpacing traditional publication methods and many recommendations are no sooner published than they are “outdated” as newer data re-shapes the therapeutic landscape.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.
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.
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
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.
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).
Briefly noted: A recent retrospective study (AA Butt et al. Gastroenterol 2019; 156: 987-96) utilized a Veterans HCV database (n=242,680) and determined that HCV therapy improved cardiovascular outcomes.
Key finding: Treatment with a direct-acting antiviral regimen lowered the risk of cardiovascular events by more than 40% (hazard ratio of 0.57) compared to no treatment.
This finding is limited based on the reliance of a retrospective study and not being able to control for factors that may have led some patients to not receive treatment.
In two related commentaries referenced below, the authors detail how Australia and Brazil managed to provide a blockbuster hepatitis C virus (HCV) medication without following the going-broke example of Blockbuster video stores.
Australia: S Moon et al. NEJM 2019; 380: 607-9
Brazil: EM da Fonseca et al. NEJM 2019; 605-6.
Australia provided a lump-sum payment of approximately 770 million dollars (in U.S.) over 5 years in exchange for an unlimited volume of direct-acting antivirals (DAAs). As a result of this approach, Australia managed to treat many more patients at a much lower cost. “The government would have to spend …U.S. $4.92 billion more to treat the same number or it could treat 93,000 fewer patients with a fixed budget” of approximately U.S. $766 million.
With the Australian approach, the authors note that it is analogous to a patent buyout and works if the ongoing drug manufacturing cost is low and the manufacturer is able to meet growing volume demand.
Brazil’s approaches for DAAs relied on either threatening loss of patent protections and/or enabling local generic production of sofosbuvir. This resulted in ~90% price discount. Patent protection in Brazil is granted only if a medication is approved by both INPI (Instituto Nacional da Propriedade Industrial) and ANVISA (Brazilian Health Regulatory Agency).
My take: Given the rising costs of medicines, examining how other countries surmount these financial barriers is important. In my view, the often arbitrary and exorbitant pricing by pharmaceutical companies will erode the support of protective policies in the U.S. which thus far has helped produce many advances.
B Wildman-Tobriner et al. Gastoenterol 2018; 155: 1428-35. This retrospective study which pooled data from 3 phase 2a trials with 370 subjects with nonalcoholic fatty liver disease (NAFLD) found that MRI iwth proton density fat fraction (PDFF) “did not accurately identify patients with NAS ≥4 (AUROC – 0.72) or fibrosis stage ≥3 (AUROC =0.66).” Thus, this study indicates that currently liver histology remains the gold standard to determine severity of liver damage in paitents with NAFLD.
P Nahon et al. Gastroenterol 2018; 155: 1436-1450. This study looks closer at whether direct-acting antivirals (DAA) for hepatitis C could increase the risk of hepatocellular carcinoma (HCC) in patients (n=1270) with cirrhosis. The authors found that the crude 3-year cumulative incidence of HCC were 5.9% in the DAA and 3.1% in the SVR-IFN group. However, after Cox analysis, “we found no statistically significant increase in risk of HCC associated with DAA use (HR 0.89).” The authors indicated that patient characteristics (age, diabetes, reduced liver function) and lower screening intensity were the reasons for the increased crude rates of HCC.
Overall, the study shows good efficacy of this regimen with and without ribavirin, though with higher SVR12 and lower relapse with the addition of ribavirin.
The difference in response was driven almost entirely based on whether there were pretreatment NS5A resistance-associated substitutions (RASs) present.
In those with NS5A RASs the difference in response with added ribavirin compared to without was 96% vs 84%.
In those without NS5A RASs the difference in response with ribavirin compared to without was 99% vs. 96%.
If RAS testing is available and baseline Y93H is absent, then ribavirin is not likely needed
Genotyping is still important. The associated editorial (pg 969-71) labeled genotype 3 ‘the problem child in the era of direct-acting antivirals.” That is, there are still differences in treatment recommendations based on HCV genotype.