HCV and kidney transplant in the era of new direct-acting antiviral agents (DAAs)

The prevalence of patients with end-stage kidney disease (ESKD) on hemodialysis affected by hepatitis C virus (HCV) infection is 7.5% and many of these patients are on the waiting-list for kidney transplant [1]. Serum HCV positivity in kidney transplant recipients is significantly higher (around 10%) than in the general population, mostly due to the history of frequent blood transfusions, and it is related to the time on hemodialysis prior to transplantation [2]. HCV infection in renal transplant recipients is associated with increased morbidity and mortality rate and it is responsible for both hepatic and extra-hepatic complications. Chronic hepatitis and hepatocellular carcinoma are the main form of liver disease after renal transplant, while fibrosing cholestatic hepatitis, even if serious, has a more limited frequency [2, 3]. Extra-hepatic disease includes recurrent or de novo HCV-related glomerular disease, transplant glomerulopathy, acute rejection and a direct and/or indirect effect on kidney fibrosis [2, 3]. These complications usually occur earlier in HCV positive renal transplant recipients than in the negative ones, in particular transplant glomerulopathy, a condition of glomerular lesions specific to renal transplant characterized by specific histopathologic findings: at light microscopy a double contouring of glomerular basement membranes with no evidence of immune deposits, which can be detected 1 month after transplant with electron microscopy [4]. The association between HCV infection and reduced graft survival in kidney transplant recipients has still to be completely clarified and there are many factors potentially involved. Several data have demonstrated how hepatic and extra-hepatic complications after kidney transplant are responsible for reduced graft survival. Recent papers have shown that HCV positive (HCV+) patients with kidney transplant have reduced graft survival compared to HCV negative (HCV−) patients [2, 5]. Among the extra-hepatic complications, new onset diabetes after transplant, infection and cardiovascular disease are more frequent in HCV+ patients and are correlated with higher mortality [3, 5]. In 2011, the U.S. Food and Drug Administration (FDA) approved the introduction of direct-acting antiviral agents (DAAs) for the treatment of chronic HCV. DAAs consist in a group of small molecules that target the nonstructural viral proteins NS3, 4A, 4B, 5A and 5B. The administration of DAAs represents a new and effective treatment option also for ESKD and transplant patients affected by HCV infection. Up until a few years ago, the management and treatment of HCV+ patients with ESKD and kidney transplant posed a real challenge. Indeed classical treatment of HCV infection with an interferon-based regimen was associated with poor tolerability, low efficacy and unacceptably high rates of acute kidney injury, acute rejection and graft failure [5]. Currently, practice guidelines by the European Association of the Study of the Liver (EASL) [6], the American Association for the Study of Liver Disease (AASLD) and the Infectious Diseases Society of America (IDSA) [7] suggest, for patients with mild to moderate renal failure and ESKD patients affected by HCV genotypes 1 and 4, infection treatment with elbasvir/grazoprevir and ombitasvir/paritaprevir/ ritonavir or ombitasvir/paritaprevir/dasabuvir plus or minus ribavirin, while effective practice guidelines for the treatment of the remaining genotypes are still lacking. Recently, a multicenter phase-3 study (EXPEDITION-4 trial) [8] evaluated the treatment with glecaprevir/pibrentasvir regimens for infection by HCV genotypes 1, 2, 3, 4, 5 or 6 in 104 patients with chronic kidney disease (CKD) stage 4 and 5 (82% on hemodialysis), and a sustained virologic response was achieved in 98% of the treated patients, with no drugrelated serious adverse events. Even more so than in ESKD, the experience with DAAs in the treatment of HCV+ kidney transplant recipients is * Gaetano La Manna [email protected]