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

Abstract

See Article on Page 552 Potential conflict of interest: Nothing to report. 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.1 Table 1 - EMA‐ and FDA‐Approved Regimens for Treatment of CHC in Adults and Ongoing Pediatric Studies Drugs Approved in Adults Genotypes Ongoing Pediatric Studies ClinicalTrial.gov Accession Number Estimated Completion Date Data Available Sofosbuvir + ribavirin 2,3 NCT 02175758 April 2018 PK 6‐18 years of agea; efficacy and safety 12‐18 yearsb Sofosbuvir + simeprevir 1,4 Sofosbuvir/ledipasvir (FDC) 1,4‐6 NCT 02249182 NCT 02868242 April 2018 PK 6‐18 years of agea; efficacy and safety 12‐18 yearsc Ombitasvir/paritaprevir/rit (FDC) ± dasabuvir) (FDC) 4, (1) NCT 02486406 January 2023 none Sofosbuvir + daclatasvir 1‐4 Elbasvir/grazoprevir (FDC) 1,4‐6 Sofosbuvir/velpatasvir (FDC) 1‐6 aGarrison et al.7 (2016); Kirby et al.10 (2015).bSchwarz et al.8 (2016).cBalistreri et al.11 (2016); Younossi et al.12 (2016). 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.2 Despite advances in DAA therapy, treatment of children with CHC has remained based on pegylated interferon with ribavirin (PR).3 Although children will typically tolerate the side effects of IFN, its use is a challenge for the patients, their caretakers, and for the medical 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.4 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.9 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.5 The first child, a 1‐year‐old 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.6 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, new‐generation 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,7 as well as the safety and efficacy data in adolescents.8 Although the off‐label use of drugs should always be discouraged when alternatives are available, in the case of DAAs the excellent results obtained in adults and the very positive preliminary results in pediatric studies (VR rates of 97%‐100%) makes it hard to justify the continued use of PR. Extrapolation of efficacy from adult studies (an approach previously demonstrated to be effective in IFN‐based treatments), preliminary results from pediatric registration trials, and case reports describing the successful off‐label use of the regimens support the hypothesis that these new regimens should be effective and well tolerated in pediatric patients also. Clearly, a concerted effort is necessary to extend testing and approval of the most effective DAA regimens in children. Most importantly, the target of global eradication of HCV may be jeopardized if the pediatric reservoir is disregarded.