Beyond the achievement of sustained virological response after liver transplantation

Graft and patient survival are significantly lower in hepatitis C virus (HCV)-infected patients than in patients who undergo transplantation for other causes (1), because of the accelerated course of hepatitis C recurrence (2). Antiviral therapy is associated with improved outcomes among patients who achieve a sustained virological response (SVR), both in individuals with severe and mild disease recurrence (3–5). However, treatment with peg-interferon (Peg-IFN) and ribavirin (RBV) in this setting had a low efficacy (~30%) and a poor tolerability and safety profile. For this reason, over the last years, a significant proportion of HCV-infected liver transplant recipients were left with no therapeutic alternatives, progressing to cirrhosis, retransplantation or even death. The addition of the first-generation protease inhibitors (telaprevir, boceprevir) to Peg-IFN and RBV improved SVR rates in patients with genotype (GT) 1 infection (~50–70%), but it was associated with increased toxicity (6, 7). The development of direct acting antivirals (DAA) and their combination in interferon-free regimens has deeply impacted the prognosis of patients with hepatitis C recurrence (8, 9). Sofosbuvir (SOF) and Simeprevir (SMV) were the two-first DAA to be approved in the USA and Europe. Despite that this combination had not been evaluated in any clinical trial in the liver transplant setting, its use was rapidly extended in clinical practice based on the encouraging results of the COSMOS trial in immunocompetent patients (10). In fact, in the last two international meetings, accumulating reports from the use of SOF plus SMV in the liver transplant setting have been presented with overall good results (11, 12). The study by Saab et al. (13), published within this issue of Liver International, reports the results of a retrospective cohort of 30 liver transplant recipients with hepatitis C recurrence treated with the combination of SOF and SMV (without RBV) for 12 weeks. Consideration for antiviral treatment was the presence of increased transaminases and the absence of allograft rejection. Patients were treated at a median time of 6 years after LT. The majority of patients (57%) had no histological evidence of graft fibrosis (F0-F1) and 43% had been previously nonresponders after LT (two patients had even received SOF plus RBV). The authors report an overall SVR rate of 93% with two patients presenting viral relapse during follow-up (both of them with advanced liver fibrosis in the graft). The safety profile was good, with no need for treatment discontinuation, or use of supportive therapy. The authors made no specific considerations regarding immunosuppresion during treatment, except for the need of standard adjustments according to serum drug levels. Although SOF plus SMV was temporarily the only available oral regimen, this therapy is currently one more alternative in the antiviral armamentarium and has been overtaken by other antiviral combinations. Saab et al. (13) endorse the use of SOF plus SMV in the transplant setting by reporting very good SVR rates (93%) in a small cohort of 30 liver transplant recipients in a single center. Its excellent tolerability (mainly because of the absence of RBV) and its short duration (12 weeks) were also factors favouring the selection of this combination. However, it should be taken into account that patients included in this small series were “easy-to-treat” individuals (3). Whether these encouraging results could be extrapolated to more complex HCV LT recipients is less obvious. Indeed, the only two patients suffering viral relapse were previous nonresponders and had already advanced fibrosis in the graft. Real-world data from large multicentric cohorts of patients treated with SOF/SMV were presented in the last AASLD and EASL meetings (11, 12) reporting overall SVR rates around 90% and supporting the use of this combination in GT1 patients. The addition of RBV did not seem to impact on overall SVR rates in none of these cohorts, which is an important point because of the lack of controlled studies using RBVfree DAA combinations in this setting. Nevertheless, SVR was significantly reduced when considering only those patients with graft cirrhosis (85% in cirrhotics, and 77% in those with MELD>10). Moreover, SVR rates were slightly lower in individuals infected with genotype 1a than 1b (14, 15) (in the current study only G1-infected patients were included but data on the subgenotype are missing). Another major