Hepatitis C Vertical Transmission

As a Pediatric Gastroenterology Fellow I have an interest in Hepatitis C (HCV) Vertical Transmission (transmission from mother to child). I am in the midst of designing a study to look at the immune activity in mothers at the time of delivery and infants over the first 12-18 months of life. I hope to find a difference in those who become chronically infected and those infants that do not.

This study is my main motivation for taking Immunology as the study is very focused on immune function. HCV challenges both the innate and cell-mediated immune systems. We currently know little about either in the pediatric patient.

Let me share some of the background with you.

HCV is a single-stranded RNA virus in the flaviviridae family. The virus has significant viral heterogeneity, including 6 major genotypes and numerous subtypes. The most common subtypes found in the United States (US) are 1a and 1b.1 The high replication rate (1010—1012 virions/day) and error prone polymerase allows for a robust production of minor viral variants. 2 It is estimated that 3% of the world’s population is chronically infected with HCV.3 The prevalence in the US is 1.8%, making it the most common blood borne infection in the US. The prevalence in the general pediatric population varies between 0.1% and 15% worldwide.4 The US pediatric HCV prevalence is 0.2% for children less than 12 years old and 0.4% for those between 12-19 years old.5

Vertical transmission of Hepatitis C virus (HCV), accounts for the majority of new cases of Pediatric HCV. Vertical transmission rates are between 2 and 14%.6 If the mother is known to be anti-HCV antibody (Ab) positive, but is HCV RNA negative, vertical transmission is very rare.7 Several studies have shown an increased risk for vertical HCV transmission associated with maternal HIV infection and IV drug use.1, 8, 9 Maternal alanine aminotransferase (ALT) and viral load have been shown to affect vertical transmission rates, with an elevated ALT >110 IU/L and a viral load of greater than 105 copies/ml associated with an increased risk for vertical transmission.6 The European Pediatric HCV Network found an increase in vertical transmission to female infants compared to male, with females twice as likely to become infected.3 This supported Granovsky’s findings that female infants were infected more frequently than males (8% vs. 3%).10 The European Network found that the duration of rupture of membranes was longer in maternal child pairs with transmission of HCV (> 6 hours) compared to those without, although this difference was not statistically significant.3 No significant correlation has been found for the type of delivery or breastfeeding. 1, 5 Maternal HCV genotype has not been shown to impact the rate of vertical transmission.6

The diagnosis of vertical transmission, transmission of infection from mother to infant, of HCV is complicated by transplacentally acquired maternal anti-HCV antibodies that can persist for up to 18 months following delivery. Seventy percent of vertically infected infants will have a positive HCV RNA PCR by 1 month of age and 90% by 3 months of age.1 If infected, children and their mothers have identical HCV genotypes.8 The diagnosis of chronic Hepatitis C is established by 2 positive HCV RNA PCRs from serum 3 to 4 months apart in an infant who is at least 2 months of age and/or by detection of anti-HCV antibodies after the infant is 18 months old.9,1
All infants born to Anti-HCV Ab positive mothers will have circulating IgG antibodies to HCV at birth. 99% of children lose the Anti-HCV antibodies within 18 months of delivery if they are negative for HCV RNA. Chronic infection is most often asymptomatic in childhood; however elevation of transaminases is quite common.4 Typically liver disease remains mild for the first 1 or 2 decades.5 A small portion of perinatally infected children have developed advanced liver disease during childhood accounting for 9 liver transplants in North America between 1995 and 2001.5 HCV remains a leading diagnosis resulting in liver transplant in the adult population.

One study from Italy began the investigation into the role of fetal immune activity in the vertical transmission of HCV. This study demonstrated Hepatitis C virus-specific reactivity of CD4+ lymphocytes in children born to HCV-infected women. HCV-specific T-cells were more frequent and vigorous in children than in their HCV positive mothers. This study demonstrated that vertical exposure to HCV induces a Hepatitis C virus-specific cell-mediated immune response. The authors hypothesized that development of a robust HCV directed cell-mediated immune response during fetal life may contribute to the relatively low frequency of vertical transmission.14 There are no other published systematic studies of immune cell function in infants at risk for vertical transmission. Currently, there are several completed and ongoing trials investigating the immune cells function in the role of HCV clearance in adult patients.

Meyer demonstrated clearance of infection in male German youth from 16 to 24 years old with a weak HCV-specific CD4+ t-cell response.15 In this study there was no difference between acute and chronically infected subjects CD4+ response. 15 This study proposed that the low levels of viremia are controlled by the innate immunity without a strong adaptive immune response. 15

Fetal immune activity has been shown to be biased towards the Th2 response for protection of the fetal-maternal interface. The Th2 predominant response results in suppression of Th1 activity. 16 Fetal CD4+ T-cells have low cytokine production and decreased numbers of mononuclear phagocytes resulting in a weak innate immune response. While the fetal immune response to HCV has not been fully examined, the decreased Th1 activity may play a role in chronic infection resulting from vertical transmission.16

The immune response seen in chronic HCV has been shown to be weak and directed at a limited number of epitopes when compared to the response seen in spontaneous clearance.17 The immune response seems to quickly compartmentalize to the liver with evidence that HCV may upregulate homing molecules involved in T cell recruitment.17 There are conflicting reports regarding the role of HCV specific CD8+ T cells in chronic infection.17 CD8+ T cells have been associated with variable amounts of liver injury and a range of viral loads.17

Viral clearance is generally attributed to a robust induction of cell-mediated immune response including type 1 interferon, cytotoxic T lymphocytes (CTL) and natural killer cells (NK).15, 18, 19The role of dendritic cells includes viral recognition and activation of pathways for IFN – Beta production and Nk/CTL induction. The role of dendritic cells in childhood HCV infection has not yet been evaluated.18

Cytotoxic lymphocytes include cytotoxic T lymphocytes (CTLs) and natural killer cells (NK cells) that are responsible for eliminating damaged cells and play a key role in mediating host response to viral infection. CTLs are MHC-Class I restricted CD8+ T cells that migrate into affected tissue in association with the MHC Class I complex and suppress viral replication by cytolysis and secretion of antiviral cytokines. One study in adults demonstrated a functional T-cell threshold that predicted recovery from acute HCV infection.20 NK cells work through rapid and potent cytotoxic activity and by production of inflammatory cytokines, such as IFN-γ.17 NK cells provide a first line of defense against viral infections, and are critical for the development of Antigen-specific memory.19 The activity of NK cells is controlled by receptors (NKRs) that mediate activation or inhibition upon ligation of surface molecules on target cells.17, 21Alterations in NK function can create a situation where the virus may have a replicative advantage leading to a high level of viremia that cannot be controlled by memory T cells.18

CD4+ T lymphocytes regulate CTL memory via cytokine production and by assisting antigen-presenting cells. CD4+ T cells also are important in IL-2 production. In adults with HCV, levels of HCV-specific CD4-derived IL-2 were significantly higher in patients who cleared the HCV infection.20 These data suggest that CD4+ lymphocytes might play a role in the prevention of vertical transmission of HCV or the resolution of infection.

Understanding the role of cell-mediated immunity in the regulation of vertical acquisition or clearance of HCV is the first step in identifying infants at risk for chronic infection. This study will describe cell-mediated immune activity that could provide the first step in a process leading to early treatment regimens that target infants at highest risk for chronic HCV infection.

References
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