Steroid avoidance in liver transplantation: Meta-analysis and meta-regression of randomized trials

Abstract

Steroid use after liver transplantation (LT) has been associated with diabetes, hypertension, hyperlipidemia, obesity, and hepatitis C (HCV) recurrence. We performed meta-analysis and meta-regression of 30 publications representing 19 randomized trials that compared steroid-free with steroid-based immunosuppression (IS). There were no differences in death, graft loss, and infection. Steroid-free recipients demonstrated a trend toward reduced hypertension [relative risk (RR) 0.84, P ϭ 0.08], and statistically significant decreases in cholesterol (standard mean difference Ϫ0.41, P Ͻ 0.001) and cytomegalovirus (RR 0.52, P ϭ 0.001). In studies where steroids were replaced by another IS agent, the risks of diabetes (RR 0.29, P Ͻ 0.001), rejection (RR 0.68, P ϭ 0.03), and severe rejection (RR 0.37, P ϭ 0.001) were markedly lower in steroid-free arms. In studies in which steroids were not replaced, rejection rates were higher in steroid-free arms (RR 1.31, P ϭ 0.02) and reduction of diabetes was attenuated (RR 0.74, P ϭ 0.2). HCV recurrence was lower with steroid avoidance and, although no individual trial reached statistical significance, meta-analysis demonstrated this important effect (RR 0.90, P ϭ 0.03). However, we emphasize the heterogeneity of trials performed to date and, as such, do not recommend basing clinical guidelines on our conclusions. We believe that a large, multicenter trial will better define the role of steroid-free regimens in LT. Liver Transpl 14:512-525, 2008. © 2008 AASLD. The use of corticosteroids has historically been the mainstay of decreasing rejection risk following liver transplantation (LT). Steroids, however, are associated with a multitude of side effects, including diabetes, hypertension, altered lipid metabolism, decreased wound healing, decreased immune defense against infection, osteoporosis, fractures, and obesity.Another potential side effect of steroid use in LT is recurrence of hepatitis C virus (HCV). In the past decade, there has been a dramatic shift in the indications for LT, and HCV has emerged as the single most important cause of end-stage liver disease leading to LT. Although only 16% of transplants were performed for HCV-related cirrhosis in 1991, this increased to over 50% by 2001. 1 Immunosuppression (IS) in HCV patients is a fine balance between adequate IS to prevent rejection and avoidance of over-IS to prevent severe HCV recurrence. 2,3 There is also circumstantial evidence to suggest that steroid boluses result in active viral replication and more aggressive recurrence including fibrosing cholestatic hepatitis. Furthermore, the development of diabetes and hyperlipidemia associated with steroids may increase the risk of steatosis, which has been implicated in worsening the outcome with HCV. 4,5 With significantly improved short-term outcomes over the last 2 decades, 6 the current challenges in LT

Strategies to reduce hepatitis C virus recurrence after liver transplantation

“…However there is a lack of robust data showing the efficacy of this approach. A meta-analysis of 13 trials [100] showed that steroid avoidance was associated with lower HCV recurrence (RR = 0.90, P = 0.03), although no individual trial reached statistical significance. The heterogeneity, short-term follow-up and relatively small size of many of the trials, as well as the lack of information on steroid dosage, make conclusions less robust.…”

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“…57,58 There is no compelling evidence that avoiding steroids in the early postoperative period results in improved long-term outcomes; however, a recent meta-analysis noted a potential decrease in risk of HCV recurrence and cytomegalovirus infection. 59 Pulsed steroid treatment for acute cellular rejection was found, not only to be associated with transient 1-to 2-log increases in HCV RNA levels 60 ; but also, increased mortality and graft loss in this subset of recipients. 61 In a prospective randomized controlled study of 495 recipients with HCV infection, no difference was seen in the histologic recurrence rate of hepatitis C at 12 months after transplant between patients receiving cyclosporine versus tacrolimus.…”

Is there such a thing as protocol immunosuppression in liver transplantation?

“…All of these effects will contribute to higher HCV levels in the first instance and potential HCV cytopathic injury. Two meta-analyses have shown less severe HCV recurrence in CS-free protocols [12,13]; however, a large RCT showed no benefit of steroid-free IS in terms of allograft rejection, HCV recurrence or patient or graft survival [14].…”

“…Meta-analyses have demonstrated a reduction in hypertension and diabetes with steroid-free IS [12,13]. Furthermore, it is well recognized that tacrolimus therapy increases the risk of diabetes [1].…”