Treatment of hepatitis C virus infection in children: Time for action

Since 2013, 8 different direct-acting antiviral (DAA) regimens have been approved for use in adults with chronic hepatitis C virus (CHC) infection (Table 1) with excellent efficacy (sustained virological response [SVR] rates of >90%) and safety profiles. Patients historically considered difficult to treat in the interferon (IFN) era, such as adults with human immunodeficiency virus coinfection or with hepatitis C virus (HCV)–related compensated cirrhosis, can now be easily treated, achieving high virological response (VR) rates after 12 weeks of treatment. The incidence of graft dysfunction and progression to cirrhosis is higher and the overall survival rate is lower in patients transplanted for CHC when compared with patients with other liver transplantation (LT) indications, but this can now be prevented by achieving SVR before LT. Despite advances in DAA therapy, treatment of childrenwithCHChas remained based on pegylated interferon with ribavirin (PR). Although children will typically tolerate the side effects of IFN, its use is a challenge for the patients, their caretakers, and for themedical team. It is true that very few children develop end-stage liver disease due to CHC, and for most HCV-positive transplanted children, the indication for LT is a different underlying condition. Children transplanted with HCV (or who contracted HCV from the graft) have a remarkably better outcome than those transplanted because of HCV. In Italy, a national registry studying the natural course of pediatric HCV over 15 years showed that 6/332 (1.8%) children had developed end-stage liver disease at a median age of 9.6 years. In our personal experience, however, HCV infection after LT had a significant impact on these children. In this issue of Liver Transplantation, Huysentruyt et al. describe 2 children with HCV infection and cirrhosis successfully treated with ledipasvir/sofosbuvir and ribavirin for 12 weeks. The first child, a 1-yearold boy with biliary atresia, received treatment perioperatively whereas the second, a 16-year-old girl with Budd-Chiari syndrome and cirrhosis, was treated after LT. The study by Huysentruyt et al. raises up the discussion about the development and use of DAAs for children. The time frame from compound discovery to development and registration of the different regimens for adult use has been extraordinary short. This success can be ascribed in part to regulatory changes. The European Medicines Agency (EMA) and the Food and Drug Administration (FDA) agreed to permit phase 2 studies of all-oral regimens with DAAs without standard-of-care comparators, facilitating rapid drug testing and approval. The most recent regimen approved for use in June 2016 for adults with CHC was for sofosbuvir and velpatasvir. This 12-week schedule is highly effective (SVR rates of> 95%) in all patients, independently of treatment history and of the presence of cirrhosis with pangenotypic (1 to 6) efficacy. Despite these impressive results, only 4 pediatric trials are currently ongoing worldwide (Table 1). The 3 regimens tested in these trials lack the characteristics of the most recent, newgeneration treatments approved in adults with approval of these drugs in children still remote. Only limited preliminary data are available on the use of DAAs in children. Pharmacokinetics (PKs) of sofosbuvir and ledipasvir/sofosbuvir in HCV-infected children older than 6 years of age have been reported recently, as well as the safety and efficacy data in adolescents. Although the off-label use of drugs should always be discouraged when alternatives are available, in the case of DAAs the excellent results Abbreviations: CHC, chronic hepatitis C virus; DAA, direct-acting antiviral; EMA, European Medicines Agency; FDA, Food and Drug Administration; FDC, fixed dose combination; HCV, hepatitis C virus; IFN, interferon; LT, liver transplantation; PK, pharmacokinetics; PR, pegylated interferon and ribavirin; SVR, sustained virological response; VR, virological response.