Exposure to hepatitis C virus early in life : epidemiological and Immunological aspects

Hepatitis C virus (HCV) is a blood borne virus affecting the liver. Globally, it is estimated that approximately 6 million children live with HCV infection today. The main transmission route in children today is vertical transmission. Before the introduction of blood donor screening in 1992, blood transfusion was an important source of infection. The aim of this thesis was to study epidemiological and immunological aspects of exposure to HCV early in life, with specific emphasis on transmission routes.

In study I we investigated blood transfusions in the neonatal period as transmission route in chronic HCV infection. We included 230 patients born 1960-75 with chronic HCV infection. Of those, 98 had unknown and 128 had known transmission route. Four out of 230 (1.7 %) had received blood transfusion in the neonatal period. None were aware of their transfusion history at the time of diagnosis. Three patients underwent successful antiviral treatment. In study II the prevalence of HCV infection and HCV testing as well as infection outcome was studied in a cohort of 676 childhood cancer survivors in Stockholm. The prevalence of HCV testing was 34 % (233/676) for the whole cohort. Eleven out of 233 (5 %), were HCVRNA positive, which is 10 times higher than the Swedish population prevalence. A comparison of the effectiveness of screening methods showed that active tracing screening was far more effective in terms of test uptake (p < 0.001). The majority of the infected patients underwent successful antiviral treatment.

In study III we investigated the impact of IL28B genotype on vertical HCV transmission. IL28B genotype is known to be important for spontaneous clearance and interferon treatment response. We included 59 mothers with chronic HCV infection and 123 children (47 infected and 76 uninfected) born of HCV infected mothers. Neither the mothers’, nor the children’s IL28B genotype was associated with the risk of vertically transmitted HCV (HCV-VT). In study IV HCV specific T cell responses were studied in children born of mothers with chronic HCV infection. HCV specific T cell responses were investigated by IFNγ production and proliferation upon stimulation with viral antigens in vitro. We found an HCV specific T cell response in 73 % (11/15) of the mothers, 67% (6/9) of infected children and 56 % of uninfected/exposed (18/32) children. The two exposed pediatric groups had a significantly higher proportion of T cell responders compared to controls (p< 0.02). We detected HCV specific T cell responses already in exposed newborns, suggesting a prenatal exposure to viral antigens.

In conclusion, low awareness and prevalence of HCV testing in pediatric transfusion risk groups in combination with high HCV prevalence justifies active tracing screening of risk groups. IL28B genotype is not associated with HCV-VT, suggesting that other immunological factors need to be investigated. A high proportion of exposed but uninfected children have HCV specific T cell responses, suggesting that prenatal exposure to viral antigens might be more common than previously thought.

List of scientific papers

I. Einberg AP, Lindh G, Hökeberg I, Papadogiannakis N, Fischler B. Neonatal blood transfusion as transmission route in chronic hepatitis C. Transfusion. 2014; 54:1366-70.
https://doi.org/10.1111/trf.12462

II. Psaros Einberg A, Ekman A, Söderhäll S, Millbourn C, Lindahl K, Harila-Saari A, Fischler B. High prevalence of chronic Hepatitis C virus infection among childhood cancer survivors in Stockholm, Sweden. [Manuscript]

III. Psaros Einberg A, Duberg AS, Filipovich O, Nyström J, Zhirkov A, Brenndörfer ED, Frelin L, Rukoiatkina E, Lobzin Y, Sällberg M, Fischler B, Lutckii A. Lack of association between interleukin 28B polymorphism and vertical transmission of hepatitis C. J Pediatr Gastroenterol Nutr. 2017;65(6):608-12.
https://doi.org/10.1097/MPG.0000000000001711

IV. Psaros Einberg A, Brenndörfer ED, Frelin L, Hallberg L, Sällberg M, Fischler B. Neonatal exposure to hepatitis C virus antigens in uninfected children Born to infected mothers. J Pediatr Gastroenterol Nutr. 2018;66(1):106-11.
https://doi.org/10.1097/MPG.0000000000001755