Evolution of hepatitis C virus quasispecies in patients with severe cholestatic hepatitis after liver transplantation

Abstract

Evolution of hepatitis C quasispecies may be one mechanism by which fibrosing cholestatic hepatitis develops after liver transplantation. In this study, we compared changes in quasispecies complexity and/or divergence in (1) hepatitis C-infected immunosuppressed transplant recipients and in immunocompetent controls; (2) transplant recipients with mild recurrence, and in those with the most severe form of posttransplantation recurrence. Quasispecies were measured in 12 hepatitis C-infected patients pretransplantation and posttransplantation (6 with mild and 6 with severe recurrence), and in 5 immunocompetent patients with similar follow-up, and characterized by heteroduplex mobility and sequence analysis of the hypervariable region. Although the number of variants (complexity) did not change with time in either group, there was a qualitative change in the variants with time (divergence) in immunocompromised, but not in immunocompetent patients. These changes were most marked with severe recurrence, and preceded the development of severe disease. Phylogenetic analysis confirmed that most posttransplantation variants were unrelated to those detected pretransplantation. These observations suggest that in the absence of immune suppression, there is minor evolution of quasispecies. With immune suppression, divergence of quasispecies is enhanced, resulting in selection/emergence of many new variants, particularly in those with fibrosing cholestatic hepatitis. Thus, quasispecies may influence disease progression in immune suppressed populations. (HEPATOLOGY 1999;30: 1513-1520.)Hepatitis C virus (HCV)-related end-stage liver disease has become the leading indication for liver transplantation in the majority of transplant centers. 1 Unfortunately, recurrence of infection is universal 2 and recurrent HCV disease is the most common cause of chronic hepatitis after transplantation. 3,4 Although within 1 year of follow-up only about 50% of transplant recipients will develop histological evidence of HCV-related disease, 3,5 with longer follow-up, the majority of patients evolve to a slowly progressive form of chronic hepatitis. 6,7 There is a subset of patients, albeit the minority, who develops an extremely severe form of posttransplantation hepatitis, characterized by cholestasis and progressive fibrosing hepatitis, which typically results in allograft failure in less than 1 year. 8,9 Such cases have been compared with the fibrosing cholestatic variant of hepatitis B, also described in the setting of transplantation. 10

Controversies in the management of hepatitis C virus infection after liver transplantation

“…Patients with rapidly progressive cholestatic hepatitis seem to have very high levels of HCV RNA, more than 10-fold greater than the average patient with recurrent HCV, fewer quasispecies, and reduced lymphocyte recognition of HCV antigens. [9][10][11][42][43][44][45][46][47] These observations support a scenario in which the immune response to HCV is reduced, and in which the virus can proliferate rapidly without mutations. It is therefore important to note that most cases of rapidly progressive cholestatic hepatitis C seem to develop after treatment of presumed acute rejection with either monoclonal antibodies or high-dose bolus corticosteroids.…”

Genetic variability of hepatitis C virus NS3 protein in human leukocyte antigen-A2 liver transplant recipients with recurrent hepatitis C

“…37 In contrast, Sullivan et al found no differences in complexity at baseline between patients with mild or severe HCV recurrence. 35 The latter study also is in contrast with the report by Pessoa et al concerning HCV quasispecies evolution in OLT patients who develop fibrosing cholestatic hepatitis, 11 perhaps because that form of severe HCV recurrence is a completely different pathologic condition. Sanchez-Fueyo et al found that, although quasispecies complexity in the HVR-1 was similar in both OLT patients with mild or severe HCV recurrence, amino acid changes were significantly more frequent and the dN/dS ratios higher in patients with mild HCV recurrence after OLT.…”

“…[6][7][8][9] In the liver transplantation setting, some studies have also analyzed the effect of the heterogeneity in the envelope region of HCV, with discrepant results. 10,11 In contrast, the potential influence of viral variability in T-cell epitopes on the outcome of recurrent infection after transplantation has been explored only rarely. Among the relevant human leukocyte antigen (HLA)-A2-restricted T-cell epitopes mapped in the HCV polyprotein, those in the NS3 protein are commonly recognized by CD8-positive T-cells in the peripheral blood [12][13][14] and liver [14][15][16] of chronically infected patients.…”

<![CDATA[<B>CD<SUB>81</SUB> binding regions of hepatitis C virus remain conserved after liver transplantation</B>]]>

“…Our results show that in the context of a new environment and transplant related factors, which include immunosuppression and a new liver, the genetic codes of both CD 81 binding regions are kept relatively stable. Other regions of the HCV genetic code, such as hypervariable region 1 (HVR1), NS2 and NS3 have been reported to undergo considerable variability as soon as a few months after liver transplantation [19][20][21].…”