The Impact of Mode of Acquisition on Biological Markers of Paediatric Hepatitis C Virus Infection

K. England; C. Thorne; H. Harris; M. Ramsay; M.-L. Newell

Disclosures

J Viral Hepat. 2011;18(8):533-541. 

In This Article

Discussion

The impact of mode of acquisition on biological markers of HCV infection in the largest comparison of vertically and parenterally infected children to date was investigated. A significantly higher mean ALT z-score in vertically vs parenterally infected and a significantly higher mean ALT z-score in children infected before 12 months of age, regardless of mode of acquisition, was found. This latter association did not remain when only parenterally infected children were investigated which may be because of small numbers but may also indicate that the differences between groups are not completely explained by age at infection but may be related more directly to the mode of acquisition of infection itself.

Comparing biological markers of HCV infection in vertically and parenterally infected children is problematic in the light of the often substantial differences in populations in terms of age at infection, age at study entry, treatment profile, likelihood of clearance of viraemia or genotype. In the children from the cohorts studied here, four times as many parenterally than vertically infected children received HCV treatment; this may be because of more severe disease in parenterally infected children because of their age or mode of acquisition, as suggested by the finding here of a higher proportion with two or more markers of disease progression. Alternatively, their older age at diagnosis may make them more eligible for the treatment while vertically infected children, who were followed from birth, will have started on a regime of clinical monitoring without treatment. Although HCV therapy is well adhered to in the paediatric population, the unpleasant side effects and the potential impact on growth make the decision to treat a complex one.[18] There could also be bias in terms of the individual clinic or national treatment policies, especially given the continually evolving nature of information on paediatric HCV treatment and the ongoing debate about when to initiate treatment.[19]

This debate on when to initiate treatment is partly fuelled by knowledge that some children spontaneously clear viraemia without treatment. In this study, there was no effect of mode of acquisition on clearance of viraemia in contrast to some previous studies.[20] However, parenterally infected children in the UK National HCV Register were not followed up from the time of infection and possibly a large number of those who cleared viraemia did so before diagnosis or study entry. Therefore, any estimate of clearance here and elsewhere, likely underestimates the true proportion clearing viraemia in parenterally infected groups. Of note, however, the high clearance rates in parenterally infected groups are reported in this and other studies[9,21,22] which would presumably be even higher if those who cleared viraemia prior to diagnosis could be included. It may therefore be the case that parenterally infected children are more likely to clear the virus than vertically infected children but it is unlikely that this can be substantiated as follow-up from infection in parenterally infected children is rare.

No differences were found in the HCV genotype profiles of vertically and parenterally infected children in contrast to Jara et al. who found genotype 1b more frequently in children with transfusion-acquired HCV and genotype 3 more frequently in vertically infected children from seven European countries.[23] It is possible that this is because of differences in the years at which infection occurred and may reflect changes in the genotype profile of the HCV epidemic in Europe as suggested recently.[24] A higher proportion of children with genotypes other than type 1 achieved a SVR to therapy, as has been reported by other paediatric studies.[24] Additionally, in univariable logistic regression, children with genotype 1 were more likely to have consistently elevated ALT levels and consistently positive HCV RNA PCR results, although the associations did not reach statistical significance likely because of small numbers. This finding does however support those of Harris et al. who suggested that type 1 infections may be more aggressive than types 2 or 3[25] and those of a previous EPHN study which found that intrauterine vertical transmission was more likely to occur from mothers with genotype 1.[26] As no differences in the genotype profile of vertically and parenterally infected children were found here, it is unlikely that any differences in biological or clinical markers of HCV infection between groups can be attributed to the possible differences in HCV progression by genotype.

In multivariable logistic regression, no association between consistently raised ALT z-scores and mode of acquisition was found, possibly because of a lack of power, although the odds ratio remained below one, indicating higher ALT z-scores in vertically infected children. ALT levels have been shown to peak in the first 2 years of life in vertically infected children[27–29] and to adjust for this peak and any other differences resulting from age at measurement, ALT z-scores were used. The finding of increased ALT z-scores in vertically infected children adjusted for age is similar to an Australian study in which significantly higher geometric mean ALT levels in 16 vertically vs 15 parenterally infected children in the first 5 years of life were found, again after accounting for the early peak in ALT levels.[20]

Significant positive associations were found between consistently high ALT z-scores and both consistent HCV RNA viraemia and ever having evidence of hepatomegaly. There was also a higher odds of having consistently positive HCV RNA PCRs in children ever having evidence of hepatomegaly but not significantly so. The associations between these three markers of HCV-related disease progression support previous studies indicating that they may define a group of children with evidence of chronic progressive HCV or who are at increased risk of rapid or more severe progression.[2] In this analysis, similar proportions of parenterally and vertically infected children had evidence of two or more of these markers of infection. Similarly, no difference was found in the proportion with two or more markers and age at infection, in either all children or just the parenterally infected group. This lack of association with mode of or age at acquisition may have been because of combining the markers of infection into this summary variable and also the small number (15 children) of parenterally and vertically infected children with evidence of two or more markers of infection.

The prevalence of comorbidities in parenterally infected children is high given the nature of their infection during receipt of medical treatment[30] and this may have been influential in terms of the child's ability to mount an initial or continued immune response to HCV infection. In contrast, vertically infected children, although acquiring infection during immune development may benefit from persistence of maternal antibodies.[20,31] These mechanisms require specific investigation and although evidence from this analysis does not support substantial differences between the vertically and the parenterally infected groups, until they can be further defined it is important that the potential differences between them are recognized in a clinical setting. This study also highlights the growing need for epidemiological data on parenterally infected children and the difficulties in analyzing such data. Recent estimates suggest that 40% of HCV infections worldwide are acquired via unsafe medical injections and a great number of these occur in children. It is therefore vital that knowledge of disease progression in parenterally infected children is accurate and that the differences between vertically and parenterally infected groups are clarified to inform more accurate and individualized clinical management.

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