Viral Load Tied to Vertical Transmission of Hepatitis C

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Genetic variation in IL28B with respect to vertical transmission of hepatitis C virus and spontaneous clearance in HCV infected children

"In view of the data presented, we believe it is necessary to make a clear distinction between the risk factors of HCV-VT and of chronic infection. We confirm that viral load and HIV co-infection are the only risk factors involved in HCV-VT. On the other hand, the viral genotype non-1 and the infant's IL28B CC Rs12979860 polymorphism are associated with HCV spontaneous clearance. Our data are the first to account for HCV virus clearance and may provide important information about protective immunity to HCV."

Last Updated: May 23, 2011.

Hepatology

Accepted Article (Accepted, unedited articles published online for future issues)

High maternal viral load is associated with vertical transmission of hepatitis C virus, but polymorphisms in interleukin 28B are not, according to a study published online March 16 in Hepatology.

MONDAY, May 23 (HealthDay News) -- High maternal viral load is associated with vertical transmission of hepatitis C virus (HCV-VT), but polymorphisms in interleukin 28B (IL28B) are not, according to a study published online March 16 in Hepatology.

Angeles Ruiz-Extremera, M.D., from San Cecilio University Hospital in Granada, Spain, and colleagues assessed the role of a single nucleotide polymorphism on IL28B in HCV-VT and the spontaneous clearance of HCV among infected infants. Mothers recruited for the study included 112 who were HCV-RNA positive/HIV negative and 33 HCV-RNA negative/HCV-antibody positive with 142 and 43 children, respectively. Children underwent testing for HCV-RNA at birth and regularly until the age of 6 years. Single nucleotide polymorphism at IL28B was determined in mothers and children. The occurrence of HCV-VT was assumed when children presented HCV-RNA positive in two subsequent blood samples.

The investigators found that 61 percent of the 31 mothers with the CC polymorphism and 82 percent of the 68 mothers with non-CC polymorphism were HCV-RNA positive. Among infants born to HCV-RNA positive mothers, 20 percent acquired HCV infection, but only 9 percent were chronically infected. No HCV-VT was seen in HCV-RNA negative women, and the rate was increased in mothers with higher HCV viremia. Neither maternal nor child IL28B status was correlated with increased risk of HCV-VT. Genotype non-1 and genotype CC of the IL28B were the factors influencing viral clearance among the infected children. Child CC polymorphism was the sole predictor of HCV clearance in HCV genotype-1.

"High maternal viral load is the only predictive factor of HCV-VT. IL28B plays no role in HCV-VT," the authors write.

Abstract

The vertical transmission of Hepatitis C Virus (HCV-VT) is a major route of HCV infection in children, but the risk factors remain incompletely understood. This study analyses the role of IL28B in HCV-VT and in the spontaneous clearance of HCV among infected infants. Between 1991 and 2009, 145 mothers were recruited to this study: 100 were HCV-RNA+ve/HIV-ve, with 128 children, and 33 were HCV-RNA-ve/HCV antibody+ve, with 43 children. The infants were tested for HCV-RNA at birth and at regular intervals until the age of 6 years. IL28B (single nucleotide polymorphism rs12979860) was determined in the mothers and children. HCV-VT was assumed when children presented HCV-RNA+ve in two subsequent blood samples. HCV-VT infected infants were categorized as: (A) transient viremia with posterior HCV-RNA-ve and without serum-conversion; (B) persistent infection with serum-conversion. Of the 31 mothers with CC polymorphism, 19(61%) were HCV-RNA+ve whereas among the 68 mothers with non-CC polymorphism, 56(82%) were HCV-RNA+ve. 26 of 128(20%) infants born to the HCV-RNA+ve mothers acquired HCV infection, but only 9(7%) were chronically infected. The rate of HCV-VT was higher among the mothers with higher HCV viremia. No HCV-VT was detected in the HCV-RNA-ve women. Neither the mothers' nor the children's IL-28 status was associated with an increased risk of HCV-VT. The factors influencing viral clearance among the infected children were genotype non-1 and genotype CC of the IL28B. In logistic regression, child CC polymorphism was the only predictor of HCV-clearance in HCV genotype-1.

CONCLUSIONS:

High maternal viral load is the only predictive factor of HCV-VT. IL28B plays no role in HCV-VT, but IL28B CC child polymorphism is associated independently with the spontaneous clearance of HCV genotype-1 among infected children. (HEPATOLOGY 2011.)

Discussion

Vertical transmission of Hepatitis C Virus represents the mayor cause of paediatric HCV infection today, and in industrialized countries it is the most common cause of chronic liver disease in children. About 10-15% of those who are chronically infected might develop cirrhosis and eventually hepatocellular carcinoma (16, 17). HCV prevalence in pregnant women is similar to that of the general population and in general, most HCV-infected pregnant women do not have obstetric complications. At present, there are no antiviral treatment recommendations for HCV-infected women during pregnancy, or guidelines for the prevention of vertical transmission (18). Although persistent transmission of HCV from infected mothers to their infants is reported in 4-8% of cases (chronic HCV children), transient HCV perinatal infection also occurs, with a prevalence of about 14-17% (19, 20). Moreover, the maternal-infant transmission of HCV is more frequent than is generally reported, taking into account that spontaneous HCV-RNA clearance among children is more common than among adults and that in many studies the follow up of infants is incomplete; moreover, in many cases only limited data, corresponding to the first years of life, are presented (21). IFNα is currently the approved drug for hepatitis C treatment for the paediatric population. Combination therapy with IFNα or pegylated IFNα plus ribavirin has recently been approved by the US FDA-EMEA for children older than 3 years with chronic HCV infection, and clinical trials are in progress (3, 22). Although most children are asymptomatic and the associated liver damage appears to be less severe in children than in adults, they have a significantly poorer health status than community controls (23), which suggests there is a need for the services currently available for adult HCV patients to be extended to support the families of children with HCV.

Conflicting data have been reported regarding the possible role of the level of maternal HCV viremia. Some studies have shown that a high concentration of serum HCV-RNA is associated with a higher risk of transmission, although no specific cut-off value predicting or excluding transmission has been defined (11). However, other studies have found no such association, with a considerable overlap in concentrations of HCV-RNA between transmitting and non-transmitting mothers (1, 24). Moreover, maternal co-infection with HCV and human immunodeficiency virus (HIV) is associated with high maternal HCV-RNA and with a higher risk of transmission (18, 25). In the present study, we found that both the HCV-RNA concentration (over 600,000 UI/mL) and maternal co-infection with HIV were associated with a higher risk of HCV-VT. The infected infants were not HCV-RNA positive at birth but all became so within 2-4 months. These data indicate that HCV maternal-foetal transmission did not occur during gestation and, therefore, that the infants were infected during the birth. Most of the infected children were asymptomatic despite high levels of alanine transaminase, compatible with acute hepatitis. The infants that cleared the HCV virus recovered normal alanine aminotransferase levels. With respect to the type of birth, there was no significant decrease in HCV-VT among the mothers who gave birth by caesarean section versus those who did not. The data on the effect of caesarean section on the risk of HCV perinatal transmission are heterogeneous and high-quality studies of this question have not been reported. A recent meta-analysis including 8 studies and 641 mother-infant pairs suggests that caesarean section does not decrease perinatal HCV transmission from HCV-RNA+ve/HIV-ve mothers to infants (8). No relationship between HCV-VT and the maternal HCV genotype has been found. On the other hand, when we studied spontaneous clearance (children with transient viremia) vs chronic infection in infected infants, the HCV viral genotype was associated with a higher risk of chronic infection. Thus, the rate of HCV chronicity was higher for infants with viral genotype 1 than for those with genotype non-1, a finding that is in accordance with the results of Bortolotti et al. (6). The role of viral genotype and its association with HCV spontaneous clearance and chronic infection should be explored further.

The HCV-VT risk factors that have been most intensively studied, to date, are viral factors, maternal characteristics and birth mode. However, immunogenetic influence has been poorly investigated and mainly confined to HLA-class II serological polymorphisms, because of their central role in the adaptive response. Nevertheless, it has been suggested that the role of the immune defence system, as well as the relevance of the genetic background, could better explain the pathogenesis of HCV infection, and these factors have been examined (10, 11). In adult patients, genetic variations in the interleukin 28B (IL28B) gene, an innate cytokine, have been associated with the response to interferon-alpha/ribavirin therapy and spontaneous clearance in HCV genotype 1 (26-28). For this reason, we evaluated the role of IL28B polymorphism in HCV genotype 1 vertical transmission, transient viremia and chronic infection in infants. This is the first study that attempts to describe both HCV-VT and the spontaneous clearance of HCV, taking into account the influence of IL28B polymorphism in mothers and children. The data obtained indicate that the IL28B genotype of mothers and children does not influence HCV-VT. Nevertheless, in the chronic infection study, 83% of the infants with the CC genotype exhibited spontaneous clearance (transient viremia) versus only 22% of the children with a non- CC genotype. On the other hand, the maternal IL28B genotype did not influence HCV chronic infection. Multivariate analysis identified the infant's Rs12979860 CC IL28B genotype as the only factor independently associated with the spontaneous clearance of HCV. To the best of our knowledge, the present study is the first one to identify IL28B Rs12979860 polymorphism as a predictor of HCV spontaneous clearance in infants infected with HCV genotype 1 by vertical transmission. More information is now needed to understand the mechanisms that underlie this association, as well as the clinical impact of IL28B polymorphisms on HCV infection.

The multivariate analysis performed clearly shows the distinction between the risk factors in HCV-VT and in chronic infection. In HCV-VT, a high HCV viral load was independently associated with HCV-VT, thus confirming the bivariate analysis and the data previously published, by ourselves and by others. These data suggest that the maternal characteristics are more important in HCV-VT than are those of the infants. However, in the chronic HCV infection study, the multivariate analysis showed that the only factor independently associated with HCV clearance was the infants' IL28B genotype, which confirmed our hypothesis that in infected infants, the host's immunogenic influence is crucial to the HCV viral response.

Finally, all retrospective analyses have inherent limitations, but we have tried to minimize their effects. The standard method of HCV determination changed during the patient inclusion period but this factor was controlled by using the same PCR technique on all the patients studied, using a stored blood sample. Furthermore, the standard care of HIV and HCV patients also changed during the patient inclusion period; however, in this study the risk factors among the HIV negative mothers (Study Cohort) were identified. According to standard protocols for VHC pregnant women, no VHC treatment should be applied during the pregnancy, and thus the changes in standard care for HCV patients do not affect our study. In view of the data presented, we believe it is necessary to make a clear distinction between the risk factors of HCV-VT and of chronic infection. We confirm that viral load and HIV co-infection are the only risk factors involved in HCV-VT. On the other hand, the viral genotype non-1 and the infant's IL28B CC Rs12979860 polymorphism are associated with HCV spontaneous clearance. Our data are the first to account for HCV virus clearance and may provide important information about protective immunity to HCV.

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