Abstract
Hepatitis C virus (HCV) is an important cause of viral hepatitis in children and the actual number of infected children is clearly underestimated. HCV infection across the pediatric age spectrum differs from perinatal acquisition to infection acquired later in life; the modes of transmission, rates of spontaneous clearance or progression of fibrosis, the potential duration of chronic infection when acquired at birth, and, significantly, available treatment options also vary [1]. The discovery of HCV using molecular cloning techniques in 1989 led directly to an initial reduction in the number of acute HCV infections, and to the establishment of detection and treatment strategies. Mirroring the IV drug abuse epidemic, there has been a significant increase in reported HCV infections across all age groups over the last decade.
Introduction
Hepatitis C virus (HCV) is an important cause of viral hepatitis in children and the actual number of infected children is clearly underestimated. HCV infection across the pediatric age spectrum differs from perinatal acquisition to infection acquired later in life; the modes of transmission, rates of spontaneous clearance or progression of fibrosis, the potential duration of chronic infection when acquired at birth, and, significantly, available treatment options also vary [1]. The discovery of HCV using molecular cloning techniques in 1989 led directly to an initial reduction in the number of acute HCV infections, and to the establishment of detection and treatment strategies. Mirroring the IV drug abuse epidemic, there has been a significant increase in reported HCV infections across all age groups over the last decade.
Virology
The hepatitis C virus is the prototype for the Hepacivirus genus of the family Flaviviridae. The virion is about 30–60 nm in diameter. The capsid is thought to be enveloped by a lipid bilayer. The envelope contains two viral glycoproteins, E1 and E2, and the nucleocapsid contained within is composed of core protein and the viral RNA genome [2].
The genome is a 9.6 kb positive, single-stranded RNA (Figure 19.1). A single open reading frame (ORF) encodes a 3011 amino acid residue polyprotein that undergoes proteolysis to yield ten individual gene products, consisting of three structural proteins (core and envelope glycoproteins E1 and E2) and seven non-structural (NS) proteins (p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B). The core protein is highly conserved and may be involved in processes such as apoptosis, intracellular signaling, transcription, and modulation of the host immune response. Proteins E1 and E2 enable virus-host cell fusion. Unlike the core protein, E1 and E2 demonstrate considerable sequence heterogeneity from different isolates. The N-terminus of E2 contains a “hypervariable” region (HVR); HVR1 that is an important viral neutralization determinant. The sequence variability of E2 may account, at least in part, for the ability of HCV to elude the host immune system and establish persistent infection.
The 3′-region of the genome encodes the NS proteins that participate in post-translational proteolytic processing and replication of HCV genetic material. Just downstream of the E2 coding region is a small integral membrane protein, p7, which appears to function as an ion channel but also appears necessary for efficient assembly, release, and production of infectious progeny virions from liver cells. NS3/4A is a protease/helicase required for HCV polyprotein cleavage and RNA secondary structure and unwinding. NS4B is an integral membrane protein that alters membrane structure and contains a GTP-binding domain essential for HCV replication. It is also responsible for the formation of the “membranous web” structure within the cytoplasm of infected cells where HCV replication occurs [3]. NS5A is a multifunctional protein with key roles in modulating viral replication and altering the intracellular milieu in response to viral infection. NS5B encodes the RNA-dependent RNA polymerase. The flanking 5′- and 3′-non-translated regions contain conserved sequences that regulate both genome replication and translation. Six distinct HCV genotypes have been identified (see “Epidemiology”).
Viral replication is a highly dynamic process which is capable of producing ~1012 virions per day – the clearance rate is equally dynamic, such that the HCV half-life is an estimated two to three hours.
Within infected individuals, HCV circulates as quasispecies, a mixture of closely related but distinct genomes, which typically differ by 1–3%. In an infected person, quasispecies may either be present from the onset, as a result of simultaneous transmission, or may develop over time through accumulation of mutations. Such mutations may enable more efficient HCV replication or evasion of host immune responses. Certain regions of the genome, such as HRV1 in E2, are hyper-variable and responsible for most, but not all, of the genomic differences in quasispecies. Appearance of antibodies against HVR1 in infected subjects is followed by emergence of new variants in the region. For these reasons, HVR1 is believed to play a role in HCV persistence and chronic HCV infection.
Pathology
Hepatocytes are the primary site of viral replication. Entry mechanisms of HCV into the cell are not entirely understood, but data suggests that entry is mediated by specific interactions between both viral envelope proteins (E1 and E2) and a host cell surface receptor. The first identified host cell receptor was the cell surface protein CD81 [4] which is bound by E2 enabling viral entry. The identification of HCV-CD81 interaction has expanded the search for other receptors such as low-density lipoprotein receptor (LDLr), scavenger receptor class B type I (SR-BI), Claudin-I and Occludin, and CD36 which are thought to promote early stages of host cell and HCV interactions [2]. Evidence from studying other flaviviruses supports a model in which entry via receptor-mediated endocytosis is followed by envelope fusion with the endosomal membrane to release the nucleocapsid into the cytoplasm. There, ribosome binding to the viral genome enables translation of the encoded polyprotein, with the formation of a replicative ribonucleoprotein complex. The resulting negative-strand intermediate then serves as a template for the production of positive-strand RNA. Like other flaviviruses, budding of virus likely occurs into intracellular vesicles, which release free virus from the cell by exocytosis. How HCV acquires its envelope or specifically excludes cellular proteins and RNAs during virion assembly is not known.
Immunopathogenesis of Infection and Viral Persistence
Infection with HCV becomes chronic in at least two-thirds of those infected; the outcome (spontaneous clearance vs. persistent infection) is typically determined within six months of infection. Clearance occurs when the host innate immune system senses and responds to eliminate the virus [5, 6]. Individuals with acute, self-limited HCV infection have early, vigorous responses with both CD4 (T helper) and CD8 (cytotoxic) T-cells. The sequences that are recognized by HCV-specific T-helper cells are immunodominant (the NS3 protein in particular) and conserved among HCV genotypes. Major histocompatibility class (MHC) haplotypes determine the presentation and recognition of a set of common viral epitopes, suggesting that these antigens may be important in development of immune reactivity. Both HCV-specific CD4 T-cells and CD8 T-cells become detectable in blood three to four weeks after infection. Infiltration of the liver with T-cells correlates with an increase in serum aminotransferase (ALT) levels as cytotoxic lymphocytes lyse HCV-infected cells. After recovery from HCV infection, circulating HCV-specific T-helper and cytotoxic lymphocytes may be present for decades, even when the humoral response declines and HCV antibodies become undetectable [7].
More commonly, viral persistence is established through various HCV-specific immune evasive mechanisms. Interferon (IFN) and other pro-inflammatory cytokines, normally produced by host cells following viral recognition, are integral to viral eradication. However, HCV has developed multiple strategies to escape or overcome the antiviral actions of IFN including antagonizing, disrupting, and suppressing IFN signaling [6, 8]. Other key components of the innate immune system, such as toll-like receptors (TLRs), have been shown to be affected by HCV proteins, suggesting a possible role for the development of chronicity [6]. Critical innate immune cells, including dendritic cells, monocytes, and natural killer cells (NK), have all been shown to have functional impairment in patients with chronic HCV infection [9–11]. HCV successfully escapes the compliment system through inhibition and depletion of multiple components including C3, C4, and C9 [12–14]. Furthermore, HCV induces CD55/DAF as a negative regulator of complement activation [6]. Finally, HCV has been shown to modulate antigen-presenting cells (APCs) and CD4+T/CD8+T-cell function, impairing the adaptive immune response [6]. Ultimately, HCV is able to modulate the immune response in various cell populations and microenvironments, enabling evasion from host removal mechanisms and promoting the development of persistent infection.
Epidemiology
The global disease burden of active HCV infection in the pediatric population is estimated to be around five million children and adolescents with prevalence rates ranging from 0.05–0.36% in the USA and Europe to 1.8–5.8% in certain developing countries [15, 16]. However, suboptimal ascertain practices result in an underestimate of the true prevalence, since identified infected children reflect only a small fraction of expected cases [17, 18].
The economic cost of HCV infection on the healthcare system has been well documented. Before the availability of direct-acting antiviral (DAA) agents (see “Treatment” below) cost estimates ranged from $4.3–$8.4 billion (US dollars), with lifetime costs for individuals estimated at $64,490 [19]. Cost analysis by age demonstrated that younger individuals (<18 years) with infection would be expected to accrue an estimated lifetime cost of $116,540 [19].
Six distinct HCV genotypes have been identified with significant global variation. In adults, HCV genotype 1, subtypes 1a and 1b as well as genotype 2, subtypes 2a, 2b, and 2c represent the most common variants in Western countries. HCV genotype 3 is widely distributed in South and East Asia, with subtype 3a common among intravenous drug users from Europe; genotype 4 is found in North Africa and the Middle-East; genotype 5 in South Africa, and genotype 6 in Asia [20]. While all six genotypes have been identified in children, robust epidemiological reports on the disease burden in children and adolescents are lacking. When reported, it appears that affected children often demonstrate regional distribution patterns that are similar to those described in adults. For example, genotypes 1–3 dominate the HCV burden of both children and adults in the USA [21–23].
Perinatal Transmission
Once considered a transfusion-related disease, the advent of blood-bank screening practices has resulted in no new pediatric cases of transfusion-transmitted acute HCV infection in the USA since 1994 [24]. Consequently, mother-to-infant transmission during the perinatal period has emerged as the most common mode of acquisition of infection in children, accounting for approximately 60% of cases [25]. Mechanisms leading to perinatal HCV transmission are currently not well understood. Suspected risk factors include perinatal practices (fetal scalp monitoring and C-section delivery), extended exposure to maternal blood, high levels of HCV viremia during pregnancy, and co-infection with human immunodeficiency virus (HIV) [26–31], although some studies have challenged several of these assumptions [32, 33]. A meta-analysis approach concluded that maternal HIV co-infection is the most important determinant of the risk of perinatal transmission [26]. The timing of infection in the child has also been debated with some studies showing transmission occurring relatively early in pregnancy, between 24.9 weeks and 36.1 weeks [34].
While the rate of perinatal transmission of HCV has remained stable at 5–6%, from 2006 to 2012, the incidence of HCV infection among women of child-bearing age has increased 13% annually in nonurban counties and 5% annually in urban counties in the USA [35]. This raises concern about an increasing number of pregnant women exposing their infants to HCV throughout and at the end of gestation.
Unfortunately, even when maternal HCV infection is identified, most of the at-risk children born to these women remain untested [36, 37], underscoring an important challenge. Currently, universal screening for HCV is not performed routinely in pregnant women and is reserved for those who are known to engage in “at risk” activities (Table 19.1). This strategy is highly likely to miss a significant number of infected children [38, 39]. However, studies have shown that large-scale antenatal screening programs can be feasible, effective, and affordable [40]. One study demonstrated not only cost effectiveness, but also measurably improved outcomes for mothers and, most notably, increased identification of exposed neonates from 44% to 92% [41].
Table 19.1 Individuals who should be tested for hepatitis C infection
| Testing | Demographic category |
|---|---|
| Recommended | Those with a history of illicit injection drug use |
| Those with a history of persistent ALT elevation | |
| Those who have had a prior transfusion (blood or blood products) or recipients of organs before July 1992 | |
| Those requiring chronic hemodialysis | |
| Children born to HCV-positive women | |
| HIV infection | |
| Current sexual partners of HCV-infected people | |
| Healthcare and public safety workers after needlestick, sharps, or mucosal exposuresa | |
| Not recommended | Household (non-sexual) contacts of HCV-positive individuals (without additional risk factor) |
| Pregnant women without other risk factors | |
| International adoptees |
HCV, hepatitis C virus; ALT, alanine aminotransferase.
a Testing of the exposure source would be indicated and subsequent testing of the exposed worker could be undertaken if needed.
Outside of the perinatal period, additional routes of acquisition of HCV infection in children results from engagement in high-risk practices, such as intravenous drug abuse (IVDA), and intrafamilial transmission.
The Recent Surge
Intravenous drug abuse is a significant, increasingly common route of HCV infection in adolescents and young adults. Mirroring the IVDA epidemic, there has been a significant increase in reported HCV infections over the last decade, with one study demonstrating a 364% increase in HCV infection among people 12–29 years of age living in the Appalachia region of the USA [35, 42, 43]. The number of hospitalized children across the USA with HCV increased 37% from 2006 to 2012 [44]. These findings show that a new wave of young individuals will require HCV-specific treatment or risk the development of progressive liver disease and its complications. Furthermore, these data suggest a potential surge in the rate of mother-to-infant HCV transmission with resultant increased disease burden among children.
Hepatitis C virus infection has been associated with other high-risk activities including receiving tattoos in an unregulated setting, intranasal cocaine use, and engaging in sexual practices that involve multiple partners and/or sexual activity with trauma.
Co-Infection with Human Immunodeficiency Virus
Hepatitis C virus co-infection with HIV infection impacts an estimated 2.75 million people around the world, predominantly in African and Southeast Asian regions [45]. In the USA, about 10% of HCV-infected people have HIV infection as well. Approximately 25% of HIV-infected people in the Western world have chronic hepatitis C [46]. These epidemiologic data are not available for childhood infections, but rates of co-infection, at least in Western countries, is probably lower [47]. Given the lower prevalence, clinical management of HCV/HIV co-infected children is challenging. A systemic review did suggest that the more severe liver phenotype of HCV in co-infected adults may also be true for children, with HIV/HCV children having lower rates of spontaneous clearance, higher peak aminotransferase values, and accelerated progression of hepatic fibrosis; the authors noting that routine follow-up for this vulnerable population should be more consistent than that in mono-infected children [47]. Adult studies have demonstrated that HIV co-infection does not impact outcomes of newer HCV treatments and that co-infected patients should be treated the same as mono-infected persons, although attention to potential drug:drug interactions is required [45]. Current data is not available for co-infected children; however, as newer direct acting antiviral (DAA) agents are being approved for younger patients (see “Treatment” section below), pediatricians who care for these children will need to determine how to optimize management for this difficult population.
Diagnosis
The two major types of tests available for laboratory diagnosis of HCV infections are antibody assays for HCV (anti-HCV) and nucleic acid tests, usually done by polymerase chain reaction (PCR) to detect HCV RNA. Interpretation of these tests is displayed in Table 19.2. Assays for IgM to detect early or acute infection are not available. Current immunoassays for anti-HCV are at least 97% sensitive and 99% specific [1, 48, 49]; importantly however, both false positive (patients with autoimmune disease, mononucleosis, pregnancy) and false negatives (patients with hypogammaglobulinemia or immunosuppressed patients) can occur [48]. Additional false negative results can be seen early in the course of acute infection and result from the prolonged interval between exposure and onset of illness and seroconversion. Within four months after exposure, and five to six weeks after onset of hepatitis, 80% of patients will have detectable anti-HCV.
| Anti-HCV | HCV RNA | Interpretation |
|---|---|---|
| Negative | Negative | No infection |
| Positive | Positive | Acute or chronic infection |
| Negative | Positive | Early infection or chronic infection in an immunosuppressed host |
| Positive | Negative | Resolved infection or chronic infection or false positive antibody test |
In general, testing for HCV infection should be considered for all children suspected to be “at-risk” (Table 19.1). However, unique to children is the sequence of testing recommended for infants born to mothers with HCV infection who are in danger of becoming infected. Mothers infected with HCV will have circulating anti-HCV immunoglobulin G (IgG) which crosses the placenta and can be measured in the serum of their infants. Maternal antibody can persist in the child for over a year; consequently, testing for anti-HCV in infants is not informative during this period. The American Academy of Pediatrics (AAP) recommendations are to delay measurement of anti-HCV until after 18 months of age [1]. HCV RNA testing can reliably indicate perinatal transmission; however, infants should be at least two months old for this test to be reliable [1, 50]. Re-testing at 12 months should occur to confirm chronic HCV infection and to rule out the possibility of spontaneous seroconversion (see “Diagnosis” below). In the absence of evidence suggesting active liver disease, delaying testing until 15–18 months of age is likely to produce the clearest results in cases of suspected perinatal transmission (Figure 19.2).
Figure 19.2 The pattern of virologic, clinical, and serological events in children following perinatal HCV infection.
Once HCV infection is confirmed with nucleic acid testing, the genotype should be determined. Multiple types of assays are used for this purpose. Knowledge of the HCV genotype is an important factor as it can determine both the specific antiviral regimen and the length of therapy; however with the emergence of highly effective pan-genotypic DAA regimens this may become less of an issue [48].
Challenges associated with HCV testing on a global scale, including access to health care, inadequate laboratory capabilities, and a lack of data to guide country-specific hepatitis testing, are significant barriers to the identification of affected children. Recent World Health Organization (WHO) testing guidelines look to strengthen and expand current testing practices to address who and how to test for HCV infection when such obstacles exist [51].
Clinical Features
Significant morbidity from HCV infection is uncommon in children [52, 53]. Adult reported symptoms of fatigue, jaundice, dyspepsia, and abdominal pain [54–56] are rarely evident in the pediatric population. While perhaps more common in endemic areas, HCV-induced fulminant hepatic failure is infrequent, with only a single case reported out of 986 children enrolled into the Pediatric Acute Liver Failure Study Group database [57].
Most commonly, children and adolescents develop chronic HCV infection, defined as the persistence of HCV RNA ≥6 months [58, 59]. Children with chronic hepatitis C are most often asymptomatic, although mild, non-specific symptoms can occur and hepatomegaly may be found [60]. The majority of HCV-infected children have intermittent or persistent liver enzyme elevations (Figure 19.2); however, aminotransferase levels do not correlate with histological severity [59]. The characteristic histopathologic lesions of pediatric HCV infection, including portal lymphoid aggregates or follicles, steatosis, sinusoidal lymphocytes, and steatosis (Figure 19.3), have been reported with approximately the same frequency as in adults. In most children with chronic hepatitis C, inflammation is mild; in one study severe inflammation was found in only 3%, moderate fibrosis and cirrhosis in only 4% and 2%, respectively [61]. More recent data suggest that the presence of bridging fibrosis may be substantially higher, ranging from 6% to above 12% [62, 63]. Although the role of liver biopsy may thus be limited in pediatric chronic hepatitis C, it may be recommended for patients in whom a concomitant or alternative diagnosis is being considered, or in patients with comorbid conditions where hepatotoxic medications should be avoided and whenever the findings may influence treatment choices [64].
Natural History in Children and Adolescents
In children and adolescents, acute hepatitis due to HCV infection is not common [65, 66]. Reports in the adult age-bracket indicate that acute hepatitis C can be asymptomatic or can present as a typical icteric hepatitis indistinguishable from acute hepatitis A or B; development of autoantibodies such as ANA may be prominent [65, 67]. It is possible that infants infected at birth who demonstrate early viremia which abates have had an acute HCV infection from which they have recovered [1].
Chronic hepatitis C in children and adolescents can follow several different paths of progression with a variety of outcomes. One important outcome is attainment of spontaneous resolution of viremia (viral clearance) [68, 69]. Viral clearance is estimated to occur in approximately 20% of adults, whereas children have a somewhat greater chance of viral clearance [70–72]. In children with perinatal transmission, 25–40% may spontaneously undergo viral clearance, usually by age two years: this has been described as a resolution of neonatal HCV infection [1]. Another 6–12% of those with chronic hepatitis C may go on to clear the virus before adulthood [1, 63, 66, 73–75]. Spontaneous viral clearance, which is associated with biochemical remission of hepatitis, has been reported to occur more frequently in children with higher ALT levels in the first two years of life [66, 69, 76–80]. Spontaneous viral clearance has been considered a permanent state and essentially a “cure” of the HCV infection in the child; however, a case report described recurrence of viremia following seroconversion and suggests that a more nuanced approach to the care of these children may be warranted [73]. It may be more accurate to recognize that late relapse can occur but is rare (<1%) [81].
Both host and viral factors have been associated with the attainment of spontaneous viral clearance; these include infection with genotype 3 and the interleukin 28B rs12979860 single-nucleotide polymorphism [69, 76, 82, 83]. Additionally, several genetic factors of the mother or child including HLA class I, class II, and killer-cell immunoglobulin-like receptor (KIR) and KIR-ligand binding polymorphisms have recently been linked to mother-to-child transmission, as well as establishment of chronicity or clearance of HCV infection in the child [84]. A separate study identified significant differences in circulating NK cells (CD56+CD3−), along with other lymphocyte phenotypes, in children with chronic HCV infection compared to healthy controls, underscoring the potential importance of immune system differences in HCV-infected children [85].
In children with chronic hepatitis C who fail to clear the virus, liver disease is typically mild, with little evidence of progression. This pattern has been validated in numerous studies [1, 54, 59, 86–89]. One study, which included up to 35 years of follow-up, established that HCV infection acquired early in life typically shows a slow progression and mild course and outcome, in the absence of other risk factors, such as obesity [90]. In a separate study from Japan, spanning 30 years in children primarily infected via perinatal transmission, no children developed cirrhosis or hepatocellular carcinoma [63]. However, another study from the UK portrays chronic hepatitis C acquired in childhood as less benign: in long-term follow-up of 1,049 patients, 32% of patients had cirrhosis at a median estimated duration of infection of 33 years (range 12–53 years). How the HCV infection was acquired made no difference to this evolution of liver disease [91].
Potential for Progression
Hepatocellular damage with the development of fibrosis related to HCV infection can occur in childhood; however, advanced liver disease is uncommon before adulthood [90, 92–96]. Nevertheless, disease progression can be hastened in the presence of certain risk factors. In adults, more rapid disease progression has been shown to be affected by viral load, gender, ethnicity, obesity, toxins, and other environmental factors. Co-morbidities including hemolytic anemia, malignancy, immunosuppression, HIV and HBV co-infection, and certain genetic factors identified by single-nucleotide polymorphisms may also promote progression [97]. Similarly, children with co-morbid conditions such as obesity, HIV and HBV co-infections, cancer, and anemia are at risk of more severe disease [1, 98, 99]. In addition, high-risk behaviors are associated with poor outcomes of chronic hepatitis C, including alcohol use and intravenous drug use. Adverse social conditions such as homelessness or incarceration are associated with poor outcomes [80, 100–103].
Complications from chronic HCV-related liver disease in children and adolescents such as portal hypertension, ascites, variceal bleeding, and hepatocellular carcinoma, although uncommon, have been reported [86, 104–107]. Decompensated cirrhosis in children as young as four years of age has been described [61, 92, 107, 108]. The risk for developing hepatocellular carcinoma (HCC) may be increased with concurrent diabetes, obesity or steatosis, but additional data are needed [99].
Non-Hepatic Consequences
Extrahepatic manifestations of chronic hepatitis C occur in up to 74% of adults and contribute significantly to health care costs (16, 109, 110). Similar manifestations are less prevalent in children with chronic hepatitis C. Membranoproliferative glomerulonephritis, the most common renal disease associated with HCV infection in adults [111], has been reported in only three children [112–114]. Thyroid dysfunction and thyroid autoimmune disease are rare, but detectable thyroid-specific antibodies, subclinical hypothyroidism, and autoimmune thyroiditis have been described in children [115–117]. Development of non-organ specific autoantibodies, such as ANA, is well recognized [115, 116, 118–120], although their clinical significance is debated [116, 121]. Chronic hepatitis C has been associated with insulin resistance which may improve after viral clearance [81, 122]. Finally, some manifestations, such as the cutaneous features of vasculitis and porphyria cutanea tarda described in adults, have not been reported in children [54, 123].
Hepatitis C virus infection in children has also been suggested to affect both health-related quality of life and cognitive functioning adversely; however, these findings need to be confirmed in larger cohorts [124, 125]. Pediatric patients with chronic hepatitis C may experience social stigma, in part because hepatitis C is associated with intravenous drug use and in part because of fear of virus transmission in ordinary social settings. Whether this issue, as well as other stigmata, abate after viral clearance (cure) has not as yet been investigated adequately in children and adolescents.
Treatment
In this section we will focus on the management of chronic HCV infection specific to children and adolescents; however pediatric treatment trials are in process and the strategies are in flux as antivirals emerge.
In adults, newer direct-acting antivirals (DAA) agents have been trialed and shown to be highly effective for the treatment of acute HCV [126, 127]. Given the rarity of acute HCV infection in children, there is a paucity of data to inform clinicians as to when and how to initiate therapy.
The general goals of treatment in children mirror those of adults; mainly, to eradicate the virus, induce a remission of liver injury, prevent transmission, and ultimately avert and improve the outcomes relating to chronic inflammation and liver injury by decreasing or eliminating the development of fibrosis, cirrhosis, and hepatocellular carcinoma. The development of new antivirals has ushered in an era of well-tolerated medications with high efficacy. Recent cure rates attained with the use of DAAs in adults enabled optimism for affected children, and while fewer studies have investigated pediatric cohorts, emerging data suggests equal efficacy in younger populations.
Current Status of Hepatitis C Virus Treatment in Children and Adolescents
The new era of DAA therapy has enabled dramatic changes in the medical management of adults with HCV. Ever evolving treatment regimens are available that reliably achieve a >95% “real world” cure rate for all HCV genotypes [128]. Furthermore, efficacy has also been demonstrated in historically difficult to treat populations such as patients with pre-treatment cirrhosis, renal disease, patients previously exposed to antiviral therapy, prior null responders, those with HIV co-infection, and patients following organ transplantation [129–133].
Despite these advances, DAAs have been slow to be licensed and approved for pediatric use. Therefore, a review of historical antiviral therapy, including ribavirin (RBV) and pegylated-interferon (PEG-IFN), is warranted. While sustained viral responses (SVR) have improved over the last several decades from ~16% with IFN monotherapy to >50% with the combination of RBV and PEG-IFN, multiple studies have shown that SVR rates remain frustratingly low compared to more recent DAA regimens [23, 128, 134–150]. Further complicating the use of PEG-IFN treatment are the known side effect profiles. Adverse events such as anemia, neutropenia, leukopenia, and thrombocytopenia have been reported in up to 52% of those treated leading to a discontinuation rate of 4% [137]. Therapy has also been shown to negatively affect body weight, linear growth, and body composition, putting children at risk for developmental blunting [151]. However, follow-up studies have not observed any long-term effects on height-for-age z scores that could be attributed to HCV treatment [152]. Neuropsychiatric disturbances such as mood alteration, irritability, agitation, and aggressive behavior have been reported in up to 30% of children [153]. Depression, anxiety, and suicidal ideation have been reported as well [23, 144].
Several studies have suggested that certain factors may predict a more favorable response to PEG-IFN/RBV therapy, including host characteristics such as the IL28B polymorphisms, having genotype 2 or 3, and mode of transmission (iatrogenic vs. vertical transmission) [148, 153–156]. Ultimately, the treatment of HCV-infected children with IFN and RBV regimens, with their well-documented toxicities, inconvenient modes of administration (subcutaneous IFN injections), longer durations of treatment, and poor overall efficacy often leaves pediatric hepatologists searching for alternatives. More often than not, this results in the deferring of treatment in expectation of increased availability of DAAs in children. Recently published guidance suggests that the regimen of PEG-IFN/RBV should not be utilized [159].
The first study assessing the IFN-free treatment of HCV-infected children was a phase 2, multicenter, open-label study to evaluate the efficacy and safety of ledipasvir–sofosbuvir in 100 adolescents (age 12–17 years) with chronic HCV genotype 1 infection [157]. Each subject received a combination tablet of 90 mg ledipasvir and 400 mg sofosbuvir once daily for 12 weeks. The primary efficacy endpoint was the percentage of patients with a sustained virologic response 12 weeks post-treatment (SVR12). A majority of subjects (80%) were HCV treatment naïve, and 84% were infected through perinatal transmission. Overall, 98% of patients reached SVR12 and no patient had virologic failure. The two subjects who could not be considered to have reached a SVR12 were lost to follow-up either during or after treatment. No serious adverse events were reported; commonly reported events were headache, diarrhea, and fatigue [157]. In a second study, the combination of 400 mg once daily sofosbuvir and weight-based ribavirin twice daily in 52 adolescents (age 12–17 years) with HCV genotypes 2 or 3 showed SVR12 in 98% (51/52) of participants [158]. Again, the majority were treatment naïve (83%) and acquired their infection in the perinatal period (73%). The single patient in this study who did not achieve SVR12 was lost to follow-up after achieving SVR4. The most commonly reported adverse events were nausea (27%) and headache (23%) [158]. The results of these studies led to the European Medical Agency and Food and Drug Administration approval of the fixed dose combination of ledipasvir/sofosbuvir and the combination of sofosbuvir and ribavirin for the treatment of adolescents (12–17 years or weighing >35 kg) and chronic HCV genotype 1, 4, 5, and 6 and genotype 2 and 3 infections, respectively [159]. A summary of the published DAA experience in children is presented in Table 19.3. A recent cost-effectiveness study modeled DAA treatment in a hypothetical cohort of 30,000 adolescent patients with chronic hepatitis C at age 12. When compared to models that deferred treatment until adulthood, early treatment appeared cost effective, suggesting future efforts to increase the number of treated children are needed [160].
| Author, Year Published | Participant Age in Years (n) | HCV Genotype | Therapy (duration) | SVR12 (%) |
|---|---|---|---|---|
| Published manuscripts | ||||
| Balistreri et al. 2016 [157] | 12–17 (100) | 1 | Ledipasvir 90 mg + sofosbuvir 400 mg (12 weeks) | 98 |
| Einsiedel et al. 2016 [183] | 4 (1) | 1 | Ledipasvir 90 mg + sofosbuvir 400 mg (8 weeks) | 100 |
| Wirth et al. 2017 [158] | 12–17 (52) | 2 or 3 | Sofosbuvir 400 mg + Ribavirin (Variable) | 98 |
| Hashmi et al. 2017 [184] | 5–18 (35) | 1 or 3 | Sofosbuvir 400 mg + Ribavirin (Variable) | 97.1 |
| Murray et al. 2018 [185] | 6–11 (90) | 1 | Ledipasvir 45 mg + sofosbuvir 200 mg (12 weeks) | 98 |
| El-Karaksy et al. 2018 [186] | 12–18 (40) | 4 | Ledipasvir 90 mg + sofosbuvir 400 mg (12 weeks) | 100 |
| Leung et al. 2018 [187] | 12–17 (38) | 1 or 4 | Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir ± Ribavirin (Variable) | 100 |
| Alkaaby et al. 2018 [188] | 7–18 (22) | Ledipasvir + sofosbuvir ± Ribavirin (Variable*) | 90.9 | |
| Tucci et al. 2018 [189] | 0.5 (1) | 4 | Ledipasvir 22.5 mg + sofosbuvir 100 mg (12 weeks) | 100 |
| El-Shabrawi et al. 2018 [190] | 6–12 (20) | 4 | Ledipasvir 45 mg + sofosbuvir 200 mg (12 weeks) | 95 |
| Quintero et al. 2019 [191] | 6–18 (9) | 1 or 4 | Ledipasvir + sofosbuvir (Variable*) | 100 |
| Ghaffar et al. 2019 [192] | 8–18 (40) | 4 | Sofosbuvir + daclatasvir (Variable*) | 97.5 |
| Fouad et al. 2019 [193] | 11–17.5 (51) | 4 | Ledipasvir 90 mg + sofosbuvir 400 mg (12 weeks) | 100 |
| Rosenthal et el. 2020 [194] | 3-<12 [54] | 2 or 3 | Sofosbuvir and Ribavirin (variable*). 12 weeks | 98 |
| Schwarz KB et al. 2020 [195] | 3-<6 [34] | 1 or 4 | Ledipasvir-Sofosbuvir (variable*) 12 weeks | 97 |
SVR12: sustained virologic response at 12 weeks post-therapy.
* Dependent on age, fibrosis stage, genotype, and treatment experience.
** SVR 4 reported.
Recent recommendations from position papers by the Hepatology Committees of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition are summarized in Table 19.4 [159,160]. Also, as has occurred in adults, the rate of discovery is outpacing traditional publication methods and many recommendations are no sooner published than they are “outdated” as newer data becomes available that re-shapes the therapeutic landscape. To combat this challenge in the adult population, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) partnered to create an updated web experience resource to facilitate easier and faster access to treatment information (www.hcvguidelines.org/). As of this writing, a similar “living” document was not available for pediatric populations, thus care teams should be cognizant of the most current published data and increase their awareness of upcoming studies “in the pipeline” that may soon be available.
Table 19.4 Recommendations from the Hepatology Committee of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition
| Topic/Question | Recommendations (grade and strength of recommendation*) |
|---|---|
| Goal and endpoint of HCV therapy |
|
| Indications for treatment: who should be treated? |
|
| Patients Group 1: treatment of chronic HCV infection in adolescents |
|
| Treatment of HCV genotype 1 or 4 infection |
|
| Treatment of HCV genotype 2 or 3 infection |
|
| Patients Group 2: treatment of chronic HCV infection in children younger than 12 years |
|
* Evidence was evaluated by the authors and classified as high (A), moderate (B), or low (C) quality according to the Grading of Recommendations Assessment, Development and Evaluation system [196]. The strength of recommendations in the Grading of Recommendations Assessment, Development and Evaluation system was classified as outlined in Supplemental Table A of reference [159].
The general management of children and adolescents with HCV infection includes more than just antiviral therapy (Table 19.5). As progression of HCV infection can occur in children and adolescents it is appropriate to ensure consistent monitoring of these patients to ensure timely intervening measures can be taken. Sequential testing of serum aminotransferase levels and regular office visits to assess for evidence of disease progression or complications is suggested. In adults with chronic hepatitis C infection, recent advancements have enabled the validation of both circulating biomarker tests and vibration-controlled transient elastography in determining the stage of fibrosis [161–166], progression and regression of fibrosis [167–169], as well as their use in determining liver-related complications and overall survival [170, 171]. Validation of these technologies in children and adolescents is emerging; however, the low incidence of progressive hepatitis C infection in the pediatric population will require large cohorts with extended follow-up to determine their efficacy. Ultimately, the most adept approach to fibrosis assessment in children and adolescents with chronic hepatitis C infection will likely combine biomarker assessment, physical exam findings, and vibration-controlled transient elastography. In patients who demonstrate a more severe clinical course with the development of fibrosis, early DAA treatment should be pursued. Furthermore, in patients with cirrhosis, hepatocellular carcinoma can occur and regular ultrasound and alpha fetoprotein surveillance should be considered [105].
| Clinical aspect | Recommendation |
|---|---|
| To avoid transmission | HCV-infected people should avoid sharing toothbrushes and dental/shaving equipment and cover bleeding wounds |
| Stop any illicit drug use; avoid sharing/reusing needles and syringes if continuing | |
| HCV-infected people should avoid donating blood, semen, or body tissues | |
| HCV-infected people should be counseled regarding sexual transmission; those in long-term relationships are at low risk for HCV transmission;a all others should use effective barrier methods | |
| To minimize progressive liver disease | Assure vaccination against hepatitis A and hepatitis B viruses |
| Avoid alcohol | |
| Minimize obesity | |
| In selected patients, targeted therapy for HCV will decrease risk for progressive liver disease |
a Barrier methods can further lower risk even among individuals in long-term relationships.
In addition, a “liver-healthy lifestyle” should be discussed early in the course of HCV infection in children and adolescents focusing on appropriate lifestyle choices, prevention of obesity, avoidance of alcohol, and proper medication management. Because of the high rate of severe hepatitis in patients with chronic liver disease from HCV infection who become co-infected with hepatitis A or B virus, all patients should be immunized against hepatitis A and hepatitis B.
Liver transplantation for HCV-related liver disease is rare in children and adolescents, accounting for less than 1% of cases. When transplantation is required, outcomes are generally good. In an analysis of the UNOS database assessing outcomes in children who received a liver transplant for complications related to HCV, one- and three-year graft survival rates were reported to be 89.7% and 76.2% and one- and three-year patient survival rates were 97.5% and 89.4%. Re-transplantation, mainly due to disease recurrence, was reported in 10% [172].
Future Directions
Despite the success of DAA agents in adults, and the data which suggests similar safety and efficacy in children, there remain additional avenues of pursuit in the march toward eradication of HCV worldwide.
In addition to expanding pharmaceutical options and determining optimal antiviral regimens, strategies aimed at improving diagnosis, identifying patients who would benefit from treatment, and eliminating perinatal transmission from mother to child are needed to optimize the overall management of HCV in children. Finally, and in parallel, is the continued march toward the development of a broadly directed HCV vaccine that would target both humoral and cellular immune responses and assist with worldwide viral eradication.
The majority of children and adolescents with HCV remain undiagnosed, therefore enhanced efforts focused on case identification are needed so that patients can be appropriately managed. While universal screening for adults of a certain age is recommended [173], no such guidelines exist for children. One large study investigating the prevalence of HCV in urban children suggested that screening is not warranted [174]. However, this study was undertaken prior to the explosive IVDA epidemic and the dramatic increase in HCV infection among young people [35, 42, 43]. Increased patient identification must be followed with a linkage to care that enables patients to receive evaluation and treatment by an experienced healthcare provider [175].
Strategies aimed at preventing perinatal transmission will also be impactful. Recent data has demonstrated that reductions in perinatal transmission of HCV can be achieved in select populations. Mothers with HCV-HIV co-infection who were treated with combined antiretroviral therapy (cART) at the time of delivery demonstrated a lower rate of HCV transmission to their newborns than has historically been described [176]. Additional advances seen in the prevention of mother-to-child transmission of hepatitis B infection during pregnancy [177] suggests that future efficacy and safety data will be informative as it relates to newer anti-HCV therapies during pregnancy and the prevention of perinatal transmission of the HCV.
Vaccine Update
Improved treatment regimens, greater disease awareness, improved access to care, and lower cost will undoubtedly decrease the global disease burden of HCV infection. However, no virus to date has been globally eradicated without the development of a prophylactic vaccine. A preventative vaccine is needed to stop HCV transmission to uninfected individuals, and to those who are cured with DAA but remain at risk for re-exposure and persistence of infection [178]. Major obstacles to HCV vaccine development are the diversity of the virus, the ability of the virus to evade the immune response in infected individuals with high rates of mutation, and development of “quasispecies” which are distinct, but closely related HCV variants that can be present in a single individual [175, 178, 179]. Despite these challenges, a number of investigations have demonstrated success in preclinical animal studies showing induction of both humoral and cellular immunity against HCV [180, 181]. Although promising preliminary results had been demonstrated in trials conducted in humans based in part on these finding (182), results from a phase II human clinical trial (ClinicalTrials.gov NCT01296451) were not found to be effective in in preventing chronic HCV infection in adults. Ultimately, the path to a successful preventative vaccine requires comprehensive evaluation of all aspects of protective immunity, innovative application of state-of-the-art vaccine technology, and properly designed clinical trials that can affirm definitive endpoints of safety and efficacy.
References
Related posts:
Chapter 5 – Cirrhosis and Chronic Liver Failure in Children
Chapter 13 – Familial Hepatocellular Cholestasis
Chapter 16 – Diseases of the Gallbladder in Infancy, Childhood, and Adolescence
Chapter 26 – Cystic Fibrosis Liver Disease in Children
Chapter 32 – Lysosomal Storage Disorders in Children
Chapter 43 – Liver Transplantation in Children: Indications and Surgical Aspects
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