Sustained HCV Clearance after UCBT with New Direct Acting Antivirals and Development of HCV Specific Donor T Cells

Hepatitis C virus (HCV) infection increases the non-relapse mortality risk after HSCT. Oral direct-acting antiviral (DAA) drugs Simeprevir, an NS3/4A protease inhibitor, in combination with Sofosbuvir, a nucleotide analogue inhibitor of NS5G polymerase are replacing the standard therapy of interferon (IFN) and ribavirin (RBV). Here, we present the first case report of a pediatric patient with very high HCV viral load after an UCBT who was treated with Sofosbuvir and Simeprevir. The patient had an early virologic response (EVR) and developed HCV-specific CD3+ T cells. A 4 yr. old girl was referred for relapsed B-lymphoblastic leukemia in CR3. HCV antibody was negative but nucleic acid test was positive. HCV RNA PCR was elevated at log 7.2 (Fig 1). Genotype was HCV-1a subtype with unfavorable variants for IL28BS but NS3 genotype was negative. Liver US was normal and LFT was not significantly elevated. Liver biopsy was negative for fibrosis and cirrhosis but demonstrated moderate hepatitis. Patient underwent a single 4 of 6 UCBT (10.6 x107 TNC/kg) using TBI, fludarabine and cyclophosphamide. GVHD prophylaxis included cyclosporine (CSA) and mycophenolate mofetil (MMF). Engraftment occurred on D13. Sinusoidal obstruction syndrome (SOS) developed on D20-33 and treated with defibrotide. HCV treatment was initiated on D75 with Sofosbuvir and Simeprevir. Weekly PCR for HCV RNA demonstrated ∼2log decrease (Fig 1) despite remaining on CSA. Viral specific immune response to HCV was evaluated using donor specific HLA-A restricted tetramer. The patient was HLA-A*32:01/30:02 and received an UCB with HLA-A*3:01/30:01. Using HLA-A*03:01 restricted tetrameter for HCV epitope KLVALGINA, we identified HCV specific donor T cells. CDR3 regions are being sequenced to determine whether the T cell response is oligoclonal or polyclonal. The availability of the new, highly effective oral DAA HCV medication allows for IFN-free therapy and will impact the treatment for HCV after HSCT. The ability to clear the HCV and maintain viral remission will significantly decrease the risk of developing cirrhosis, hepatic failure and hepatocellular carcinoma.