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• W2921624841 abstract "Even though in many areas of the world the implementation of Hepatitis B Virus (HBV) vaccine programmes led to a significant decrease of HBV transmission, in developing countries this infection continues to be highly endemic. In the face of a specific active and passive immune-prophylaxis at birth, the risk of transmission from Hepatitis B e antigen-positive mothers is in fact still not eliminated. This may be explained by a significant percentage of children who simply may not have access to the vaccine or cannot return for the planned booster doses and/or by mothers’ exceedingly high serum viral loads 1. Once these newborns are infected, a still puzzling age-specific and HBV-restricted immune tolerance keeps under control the immune-mediated liver disease and liver function, and also prevents viral clearance. As a consequence most of the perinatally infected children will became asymptomatic chronically HBV-infected individuals, and fall under the umbrella term of the immune-tolerant HBV infection. This term has recently been changed into Hepatitis B e antigen-positive/negative infection by the European Association for the Study of Liver (EASL) recommendations 2. Although up to one-seventh of infected children spontaneously lose their Hepatitis B e antigen every year and most of them become inactive carriers before adulthood, still, some may develop progressive disease with an increased risk of liver failure or hepatocellular carcinoma 1. In spite of two classes of drugs presently available, for these immune-tolerant individuals unfortunately no effective treatment exists (Fig. 1). Treatments consist in a finite course of therapy with interferon or pegylated interferon, and a presumably long-term/non-finite and drug resistance burdened course of therapy with nucleos(t)ide analogues. These drugs may in effect benefit solely a part of those patients who have active viral replication and have blood and histological signs of active liver inflammation. This category is in the so-called immune active phase of HBV infection which has been renamed Hepatitis B e antigen-positive hepatitis according to EASL recommendations 2. The article of El-Raziky et al. 3 in this issue of the Journal is timely and emblematic of the problem posed by some of the above circumstances in Egypt, an area with intermediate endemicity and excellent paediatric HBV vaccination coverage achieved since immunisation was implemented in late 1992. However, the HBV screening of pregnant Egyptian women is still not routinely performed so that perinatal transmission still occurs and represents in that country a major transmission mode. The well-conducted study by El-Raziky et al. 3 aimed to assess the eligibility of Egyptian children with HBV infections for treatment according to the current International guidelines. These are based on HBV DNA concentration, serum transaminase concentration and severity of liver disease as assessed by either non-invasive methods or liver biopsy, as correctly summarised by the Authors in the design of their study. Approximately half and one-quarter of 103 enrolled patients resulted to have the Hepatitis B e antigen-positive and the Hepatitis B e antigen-negative chronic infection, respectively; 11% had the Hepatitis B e antigen-positive chronic hepatitis. They ended up with only two of the 103 children with chronic hepatitis B being truly eligible for treatment according to the current guidelines. The data of El-Raziky et al. 3 thus confirm that the largest part of the paediatric population with chronic HBV has not an available treatment at hand. Which news may we expect on the horizon regarding the optimal management strategy for these children with immune-tolerant chronic hepatitis B virus infection? Well, in our opinion, based on recent premises that have put the accent on three possible modalities (dual therapy with interferon plus direct antivirals association, therapeutic vaccines and immune-based therapies) alternative to the two classes of drugs available today, expected news are not yet entirely good news (Fig. 1). During the last months of 2018, three papers on dual therapy in immune-tolerant patients appeared in 2 first rank hepatology journals. One showed that in adults a lead-in strategy of 8 weeks of entecavir followed by a combination of pegylated interferon and entecavir therapy for 40 weeks conducted within the Hepatitis B Research Network (HBRN) had limited efficacy 4. In children, the paediatric group of the above network showed that the combination of entecavir and pegylated interferon for up to 48 weeks rarely led to loss of Hepatitis B e antigen with sustained suppression of HBV DNA and was associated with frequent treatment – adverse effects 5. One study conducted by others in a smaller paediatric series however obtained better results 6. Conclusions remain therefore still fluid and the last word cannot be pronounced yet. In the meanwhile, in the experts’ opinion, it may be best to advocate not treating immune-tolerant children outside of clinical trials until definite and conclusive data are available from larger prospective and multicentre studies. Therapeutic vaccines are another modality. The usual prophylactic vaccine based on neutralising antibodies directed against Hepatitis B surface antigen unfortunately is not adequate for HBV clearance. A therapeutic vaccine in fact requires potent HBV-specific CD4 and CD8 T-cell responses for contributing to the HBV clearance. To this end, several studies have under evaluation a number of candidates including less tolerogenic HBV component proteins as epitope antigens (e.g. Hepatitis B core antigen, or polymerase), Hepatitis B surface antigen-pulsed dendritic cells, and novel adjuvants other than alum, which are able to direct Th1-slanted anti-HBV immune responses. Pretreatment with antivirals to reduce viremia and liver inflammation and protein priming with recombinant HBV antigens to induce HBV-specific antibodies and prime T-cell responses are other tested modalities. Finally, boosting with a recombinant viral vector vaccine (e.g. modified vaccinia virus Ankara, MVA) encoding HBV antigens or cytokines combined with adjuvant vaccines into a single preparation have also been studied. Palpable clinical success however is still lacking. Hopefully, the translation of therapeutic vaccination from animal models to human clinical applications is in the near future 7, 8. The last modality is finally represented by immune-based therapies. Among the inducers able to activate and/or alleviate the repression of antiviral immunity there is more than one player 7, 9. The agonists of STING (stimulators of interferon genes) are able to suppress HBV by increasing Type I Interferon expression and activation of the nuclear factor kappa-light-chain-enhancer of activated B cells pathway 10. The agonists of the toll-like receptor 7 (e.g. GS-9620) have been shown to decrease HBV DNA and Hepatitis B surface antigen in HBV-infected primates but not in two double-blind phase Ib identical studies in chronic hepatitis B patients. Antibodies that block the expression of programmed death 1 (PD1) or the activity of its ligand finally were shown to increase HBV-specific T cells and produce anti-HBV-specific cytokines 7, 9. In conclusion, despite the many recent advances in treatment of chronic hepatitis B in adults, novel therapy strategies are unquestionably necessary to achieve the induction of optimal patients’ antiviral immune responses and maintain long-term control of viral replication, an issue that is still unanswered especially in the majority of paediatric patients who are in the immune-tolerant phase 1. At present, as paediatricians, we have to do efforts to demand and obtain a better prevention of mother-to-infant transmission of HBV. Since studies more and more confirm that antiviral treatment at third trimester to one-month post-partum significantly reduces the hepatitis B surface antigen positivity rate of infant without obvious safety concerns 7, this approach needs to be implemented. And if this first ring of the chain works, well begun is half done. The authors have no conflict of interests to declare. This study did not receive any specific funding." @default.
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• W2921624841 title "Hepatitis B virus and the paediatric liver: waiting for news on the horizon" @default.
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• W2921624841 doi "https://doi.org/10.1111/apa.14764" @default.
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