Management of HCV-Infection in Pediatric Patients Undergoing HCT: A Single-Center Experience

Background

Management of pediatric patients with active hepatitis C virus (HCV) infection undergoing hematopoietic stem cell transplantation (HSCT) is challenging. The introduction of direct-acting antiviral agents (DAAs) has changed the approach to HCV treatment in all settings, including in immunocompromised patients. DAAs offer significant advantages over interferon, which is associated with adverse events such as myelosuppression. While there is a large amount of data on efficacy and tolerability of DAAs in the general population and in some immunocompromised patient populations, few studies have explored their use and outcomes in pediatric patients undergoing HSCT. There is no consensus regarding optimal timing to start DAAs in HSCT recipients, whether treating HCV infection before HSCTor after discontinuation of immunosuppression for GvHD prevention.

Materials and Methods

We report outcomes for 5 pediatric patients referred to our center from South America to receive HSCT for hematological diseases who had active HCV infection.Three patients were male. Median age was 4 years (2-13).HCV genotypes were: 1a, 3a and 1b for 2, 2 and 1 patient, respectively. The median HCV-RNA 110,139 IU/mL (9,703-1,250,100) before treatment. Three patients developed moderate (5-10 x normal value) elevated liver transaminases, 1 patient had mildly elevated liver transaminases (2x normal value) while 1 patient had normal liver enzymes. No patients developed liver fibrosis and all were class A Child-Pugh. Diagnosis was acute lymphoblastic leukemia for 3 patients, T-cell non-Hodgkin lymphoma for 1 and severe aplastic anemia for 1 patient. Donor was matched unrelated donor (MUD) and haploidentical donor (haplo) for 3 and 2 patients, respectively. Stem cell source was PBSC for 3 (1haplo - 2 MUD) and BM for 2 patients (1haplo -1 MUD), respectively. Four patients received myeloablative conditioning consisting of TBI + etoposide and busulfan + cyclophosphamide + thiotepa for 3 and 1 patient, respectively. One patient received a reduced-intensity conditioning regimen consisting of fludarabine + cyclophosphamide. GvHD prophylaxis was obtained with: ATG+CsA + MMF,CsA + ATG, CsA + MMF + post-transplant Cy for 3, 1 and 1 patients, respectively. DAAs were started after discontinuation of immunosuppressive therapy, for 4/5 patients.The combination of drugs used was: glecaprevir + pibrentasvir (2 patients), sofosbuvir + velpatasvir and ledipasvir + sofosbuvir. One patient was not treated due to the unavailability of the drug.

Results

The median day for ANC and PLT recoverywas 13 (11-22) and 17 (12-56), respectively. Two patients developed aGvHD grade II (skin II) requiring systemic steroid therapy, 1 patient developed aGvHD grade I (skin I) requiring topic steroid. Two patients developed CMV-reactivation and required pre-emptive therapy with valganciclovir. After HSCT, all patients had a moderate increase in HCV-RNA viral load and mild elevation of transaminases (1.5-2 x normal value). No patient, including the one untreated, experienced worsening liver function or liver congestion. All patients treated with DAAs showedsignificant reduction in HCV-RNA copies at 4 and 8 weeks, achieving sustained virologic response by 12 weeks (SVR12). None of the patients experienced adverse effects related to the DAAs. Three out of the four patients who achieved SVR12 discontinued DAA therapy; response data for 1 patient is not yet available. The 3 patients who discontinued therapy remain HCV-RNA negative at a median follow-up of 5 months (1-33).

Conclusions

Treatment for HCV may not be possible prior to HSCT: a) for patients in need of urgent transplant; b) because the DAAs are off-label for patients younger than 12 years; c) due to lack of pediatric formulation for correct dosing in this population. Our experience shows that delay in starting DAAs after HSCT did not lead to deterioration of liver function, delay of the engraftment, or increase in incidence of transplant related complications or worsened overall outcomes in our patients. DAAs are effective and safe in pediatric patients with active HCV infection undergoing HSCT, based on SVR12 and confirmed with monthly virological surveillance. No data are currently available regarding the possibility of viral reactivation in patients receiving treatment before transplant. Larger studies are needed to assess the right timing of treatment based on clinical evaluations.

Wierda:Novartis: Research Funding; Numab Therapeutics: Research Funding; National Comprehensive Care Center (NCCN): Other: Financial relationship (Chair, CLL); Accutar Biotechnology: Research Funding; Kite: Research Funding; Acerta Pharma: Research Funding; Nurix Therapeutics: Research Funding; Eli Lilly: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Juno Therapeutics: Research Funding; Oncternal Therapeutics: Research Funding; Oncternal Therapeutics: Research Funding; Janssen: Research Funding; F. Hoffmann-La Roche Ltd.: Research Funding; BMS: Research Funding; Genentech, Inc.: Research Funding; AstraZeneca: Research Funding; GSK: Research Funding; Loxo Oncology: Research Funding; Cyclacel Pharmaceuticals Inc: Research Funding; Gilead Sciences: Research Funding; AbbVie: Research Funding.