The effect of corticosteroids on the recurrence of hepatitis C in patients who have undergone orthotopic liver transplantation (OLT) is unclear, and seems to differ according to how they are used. We know that corticosteroids increase serum viral load when administered to patients with chronic hepatitis C.1 Several studies have shown that use of corticosteroid boluses (high doses given intravenously) to treat rejection episodes after OLT can be harmful to HCV-infected liver transplant recipients and increase viremia, reduce time to disease recurrence, and increase severity of disease and its mortality.1 High cumulative doses of corticosteroids have been associated with an increased risk of severe outcomes that stem from hepatitis C recurrence.1 By contrast, the rapid and early withdrawal of corticosteroids after OLT (during the first few weeks following surgery) may, surprisingly, be deleterious, and lead to rapid development of fibrosis in HCV-infected recipients.2
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Now, Berenguer et al. report findings from a cohort of 90 HCV-infected liver transplant recipients who were initially treated with dual immunosuppression (corticosteroids plus ciclosporin or tacrolimus) after OLT, followed by slow tapering of corticosteroid therapy over >6 months.2 The risk of severe disease recurrence was significantly lower in this cohort than in an historical cohort, in whom treatment with corticosteroids was discontinued within the first 3 months (29% versus 48%, P = 0.02). These data promote the hypothesis that immunosuppression with low-dose corticosteroids may induce a favorable balance between the control of HCV replication and the minimization of liver damage caused by the immunological response to HCV-infected cells.
HCV-related, end-stage liver disease is the leading indication for OLT in Europe and the US. However, disease recurrence after OLT occurs universally in candidates who tested positive for HCV–RNA pretransplantation and may lead to chronic, active hepatitis, cirrhosis or cholestatic hepatitis. Cirrhosis occurs in 20–25% of transplant recipients within 5 years of undergoing OLT.3 Survival of patients and grafts after OLT, therefore, is lower in HCV-positive recipients than in HCV-negative recepients.4
Several factors are associated with the pattern and severity of HCV recurrence in transplant recipients. Virological factors, such as viral load at transplantation, viral load at the time of acute, post-transplant hepatitis, intrahepatic viral load after transplantation and viral genotype, have all been linked with the severity of HCV recurrence in the tissue graft.4 HCV is usually not directly cytopathic, and immune-system and host factors are important in the physiology and pathogenesis of graft disease. An immunosuppressed status is one of the most potent determinants of post-OLT progression of hepatitis C and induces an increase in viral load and a decrease in viral clearance.4
Ciclosporin has antiviral effects in vitro and a favorable influence on virological response to therapy when combined with interferon and ribavirin;1 however, studies have not revealed any differences between ciclosporin and tacrolimus with regard to the incidence or severity of recurrent hepatitis C.5 Data on the effect of other immunosuppressive agents, such as mycophenolate mofetil (MMF), azathioprine, antibodies to the interleukin 2 receptor and mammalian target of rapamycin inhibitors, on HCV recurrence remain controversial.1
An alternative management strategy is corticosteroid-free immunosuppression, which is safe and reduces levels of metabolic and infectious complications in liver transplant recipients who are not infected with HCV.6 However, only a few prospective, randomized studies have assessed the influence of a corticosteroid-free regimen on the recurrence of hepatitis C after OLT, and these were limited by their lack of protocol biopsies and short follow-up. Lladó et al. described the influence of a corticosteroid-free immunosuppression regimen in liver-transplant recipients with HCV infection.7 Patients were randomly allocated to receive basiliximab and ciclosporin either with (n = 46) or without (n = 43) prednisone; additionally, half of the study population required MMF because of renal insufficiency. Patients were followed up with routine liver biopsies for 2 years post-OLT. No difference between the groups was observed in the incidence of biopsy-proven acute or ductopenic rejections. The incidence of bacterial infections and metabolic complications was higher in the corticosteroid group than in the corticosteroid-free group. Portal and lobular histological activity was significantly increased in the corticosteroid group after 2 years, but no statistically significant between-group differences in fibrosis progression, HCV viremia, and survival of both patients and grafts were detected.
Klintmalm et al.8 conducted the largest, multicenter, prospective, randomized trial to date, which included 312 patients who underwent OLT for HCV-related cirrhosis. Patients were allocated to one of three treatment groups: tacrolimus plus corticosteroids (arm 1, n = 80), tacrolimus plus corticosteroids and MMF (arm 2, n = 79) and daclizumab induction plus tacrolimus and MMF (arm 3, corticosteroid-free, n = 153).8 At 1-year interim analysis, freedom from graft rejection was significantly more frequent in arm 3 than in arm 1 (93.0 
2.2% versus 81.9 4.4%, P = 0.011). However, survival of patients and grafts, freedom from disease recurrence, proportion of patients with high HCV–RNA titers and proportion of patients with an aggressive progression of disease were similar in all three groups. Acute rejection and donor age were significantly associated with hepatitis C recurrence. The 2-year follow-up of this cohort reported similar results, although the rate of progression to stage 
3 fibrosis during year 2 was reduced in the corticosteroid-free arm.9 A meta-analysis of randomized trials that focused on immunosuppression without steroids in HCV-infected liver-transplant recipients after OLT reported a significant reduction in disease recurrence in corticosteroid-free groups (relative risk 0.90, 95% CI 0.82–0.99; P = 0.03).10 Definitive conclusions on the effect of corticosteroid-free immunosuppression on disease recurrence cannot be drawn, owing to the limitations of many of studies published on this topic.
A clear understanding of the mechanisms that underlie hepatitis C recurrence and progression in HCV-infected liver transplant recipients is needed. Major, prospective, randomized trials with extended follow-up and adequate virological and histological assessments are needed. In particular, we must determine whether the effects of complete avoidance of corticosteroids are equivalent to those of slow tapering corticosteroids and low-dose corticosteroid therapy in terms of HCV disease progression.
At present, clinicians must routinely follow-up liver graft pathology and monitor fibrosis by routine biopsies and/or noninvasive tests. The ideal immunosuppression strategy remains elusive; however, the use of corticosteroid boluses for the treatment of acute rejection, and the rapid tapering of corticosteroids, should be avoided. A long-term, favorable outcome for HCV-infected graft recipients after OLT is more likely to be brought about by the development of highly effective antiviral therapies that can prevent or treat recurrent hepatitis C, than by modifications to current immunosuppressive regimens.
Practice point
- Steroids increase HCV viral load
- Bolus steroids accelerate graft fibrosis in patients with HCV
- Rapid withdrawal of steroids after OLT is potentially deleterious
- Steroid-free immunosuppression after OLT seems to slow fibrosis progression, but this strategy needs to be compared with the use of very low doses of steroids
Abbreviation: OLT, orthotopic liver transplantation.
