Impact of cyclosporine‐based immunosuppressive therapy on liver histology of hepatitis C virus–infected renal transplant patients
Authors: Leonardo L. Schiavon, Roberto J. Carvalho‐Filho, Janaína L. Narciso‐Schiavon, Denize V. Barbosa, Valéria P. Lanzoni, Maria Lucia G. Ferraz, Antonio Eduardo B. Silva
Journal: Hepatology (2008)

In the last few years, cyclosporine A (CsA) has emerged as a promising anti–hepatitis C virus (HCV) agent, probably acting by antagonizing the effect of cyclophilin B on HCV replication.1 In a recent article, Fernandes et al. explored the mechanisms of CsA inhibition of HCV in a replicon model.2 The authors concluded that CsA susceptibility in vivo may be affected by preexisting polymorphisms in the coding region of HCV nonstructural protein 5A (NS5A) and NS5B. As stated by the authors, although several studies have demonstrated that CsA exhibits a potent in vitro anti-HCV activity,3, 4 there are few data regarding the clinical relevance of this suppressive effect. Data from studies including liver transplant recipients suggest that CsA-based immunosuppressive therapy may be associated with lower risk of histological HCV disease recurrence and higher graft survival rates.5, 6 However, information about the impact of CsA on chronic hepatitis C outside the setting of liver transplantation is still lacking. Chronic HCV infection is highly prevalent among renal transplant patients,7 probably as a result of previous parenteral exposures. Preliminary data suggest that these subjects exhibit less intense portal/periportal necroinflammatory activity (PPA) as compared to immunocompetent individuals.8 The immunosuppressive therapy could arguably prevent necroinflammatory changes through various pathways, including inhibition of the release of proinflammatory cytokines and alteration of lymphocyte distribution and function. However, a direct antiviral effect of specific immunosuppressive drugs could conceivably be implicated. We sought to evaluate the impact of the immunosuppressive regimen on liver histology using data retrospectively collected from treatment-naïve renal transplant patients. One hundred and two patients were evaluated (males, 60%; mean age, 44.1 ± 9.4 years). All patients showed HCV viremia and underwent liver biopsy, irrespectively of alanine aminotransferase levels. A single pathologist analyzed all liver biopsy slides, using Scheuer's classification. Significant liver fibrosis (Scheuer's stage ≥ 2) and significant portal/periportal necroinflammatory activity (PPA grade ≥ 2) were observed in 20% and 40% of the cases, respectively. Univariate analysis of variables associated with significant fibrosis and significant activity are summarized in Table 1. Patients with significant fibrosis exhibited longer time after renal transplantation (10.0 ± 9.4 versus 5.9 ± 4.5 years, P < 0.001). No association between the stage of liver fibrosis and the immunosuppressive regimen used was noted. Conversely, individuals who presented with significant necroinflammatory activity showed longer time after transplantation and less frequent use of CsA. By multiple logistic regression analysis, longer time since renal transplantation (odds ratio = 1.135, 95% confidence interval 1.025-1.257, P = 0.015) and non–CsA-based immunosuppression (odds ratio = 3.438, 95% confidence interval 1.346-8.776, P = 0.010) were independently associated with significant necroinflammatory activity. Although the impact of immunosuppressive therapy on HCV RNA titers could not be addressed, we believe that these data provide in vivo evidence that cyclosporine may exert a beneficial effect on necroinflammatory activity of HCV-related liver disease. Additional studies are needed to prospectively assess the influence of CsA on virological parameters (for example, HCV viral load and heterogeneity of quasispecies) in patients with different HCV genotypes. Moreover, it is deemed necessary to further evaluate whether CsA reduces posttransplant HCV-related complications both in renal and liver recipients, as compared with other drugs such as tacrolimus. Leonardo L. Schiavon*, Roberto J. Carvalho-Filho*, Janaína L. Narciso-Schiavon*, Denize V. Barbosa*, Valéria P. Lanzoni , Maria Lucia G. Ferraz*, Antonio Eduardo B. Silva*, * Division of Gastroenterology, Hepatitis Section, Federal University of São Paulo, São Paulo, Brazil, Department of Pathology, Federal University of São Paulo, São Paulo, Brazil.