Everolimus for Liver Transplant Recipients: Is It Ready for Prime Time?

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believe this estimate to be conservative. Last, the cost of weekly telaprevir varies depending on contractual pricing of the institution, pharmacy, or health insurance companies ($2917–$4100). The limitations discussed are inherent to any simulation model for estimation of cost effectiveness. Nevertheless, the model used in the current study is very comprehensive and accounts for several pretreatment, ontreatment, and posttreatment aspects of diagnosis and treatment of chronic hepatitis C infection (Ann Intern Med 2012;156:263–270). Based on the current (Ann Intern Med 2012;156:263– 270) and other recent studies (Hepatology 2012;55: 1344 –1355) a new guidance was released by the US Centers for Disease Control and Surveillance expanding its current risk-based guidelines to include a 1-time blood test for all baby boomers and, for those who test positive, a brief screening for alcohol use a and a call for referral to treatment (MMWR Recomm Rep 2012;61:1– 32). With impending approval of several newer direct acting antiviral agents as add-on or alternative therapy to PEG-IFN⫹R and truncation of therapy to as few as 12 weeks in certain subgroups, greater efficacy and tolerability of non–interferon-based regimens, and more competitive pricing owing to multiple pharmaceutical companies with competing DAAs, we anticipate further improvement in the cost effectiveness of birth cohort screening. RAJ VUPPALANCHI PAUL Y. KWO Division of Gastroenterology/Hepatology Indiana University School of Medicine Indiana University Health Indianapolis, Indiana

Conflicts of interest Dr Paul Kwo has received contracted research funding from Abbott, Bayer, Bristol Myers Squibb, Glaxo Smith Kline, Gilead, Merck, Roche, and Vertex, served on advisory boards for Abbott, Bristol Myers Squibb, Gilead, Merck, Novartis, Vertex; he also received fees for Non-CME/CE services directly from Bristol Myers Squibb, Merck, and Vertex. Dr Raj Vuppalanchi has received honorarium for speaking engagements for Roche Diagnostics, Genentech, and Vertex Pharmaceuticals.

EVEROLIMUS FOR LIVER TRANSPLANT RECIPIENTS: IS IT READY FOR PRIME TIME? De Simone P, Nevens F, De Carlis L, et al. Everolimus with reduced tacrolimus improves renal function in de novo liver transplant recipients: a randomized controlled trial. Am J Transplant 2012;12:3008 –3020. The calcineurin inhibitors (CNI) such as tacrolimus (TAC) and cyclosporine are the central component of immunosuppression after liver transplantation (OLT). CNIs have been implicated as one of the contributing causes of chronic kidney disease (CKD) after transplan-

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tation. The quest for an immunosuppression regimen(s) that would eliminate or reduce the CNI dose, thereby reducing the risk of renal failure, without losing efficacy in preventing rejection or graft loss is ongoing. Sirolimus, a mammalian target of rapamycin (mTOR), was thought to be one such agent after its success in renal transplant recipients; however, data are conflicting among OLT recipients in terms of its safety and efficacy in preventing rejection, graft loss, and preserving renal function. There is emerging evidence that everolimus (EVR), another mTOR inhibitor that specifically inhibits mTOR-1, is safe and efficacious in preventing acute cellular rejection and preserving renal function among OLT recipients. De Simone et al examined the safety and efficacy of EVR in reducing or eliminating TAC compared with a standard, TAC-based regimen and published their findings in the American Journal of Transplantation (2012;12:3008 –3020). In this prospective, multicenter, open-label trial, after a run-in period of 4 weeks after OLT, 716 de novo OLT recipients stratified by their hepatitis C status and quartiles of renal function based on estimated glomerular filtration rate (eGFR) by 4 variable Modification of Diet in Renal Disease (MDRD) equations were randomized in 1:1:1 ratio to 3 groups: (1) EVR initiation with TAC elimination (TAC elimination), (2) EVR initiation with reduced exposure TAC (EVR ⫹ reduced TAC), or (3) standard exposure TAC (TAC control). Patients with evidence of graft failure (aminotransferases and total bilirubin ⬎3⫻ and alkaline phosphatase ⬎5⫻ the upper limit of normal), renal disease (eGFR ⬍ 30 mL/min per 1.73 m2; proteinuria ⬎ 1.0 g/24 hours), hepatocellular carcinoma outside Milan criteria, hepatic vasculature occlusion, or history of acute rejection were excluded. Mycophenolate was discontinued by the time of randomization and corticosteroids were continued until posttransplant month 6. In an intention-to-treat analysis, the composite primary end point of failure rate of treated biopsy-proven acute rejection (tBPAR) defined as rejection activity index ⱖ 3 according to the Banff criteria treated with antirejection therapy, graft loss, or death at 12 months after OLT was powered at 80%, 1-sided P ⫽ .0125 for noninferiority of EVR ⫹ reduced TAC versus TAC control (24% of tBPAR, graft loss or death, and a noninferiority margin of 12%). The secondary end point, change in renal function from randomization to month 12 after OLT assessed by eGFR, was powered at 90% for noninferiority (mean change ⫾ standard deviation ⫽ change in eGFR ⬃ 6 mL/min ⫾ 20 mL/min and correlation coefficient with prerandomization eGFR of 0.5, using an analysis of covariance model). Randomization to TAC elimination was terminated prematurely owing to a higher rate of tBPAR. Patients in this arm past 180 days after randomization were then assigned to standard therapy and further results were discarded. This study demonstrated that the EVR ⫹ reduced TAC was noninferior to the TAC control arm for the primary efficacy end point of tBPAR, graft loss, or

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death at 12 months posttransplantation (6.7% vs 9.7%; P ⬍ .001 for noninferiority with a 12% margin). tBPAR occurred in 2.9% of EVR ⫹ reduced TAC patients versus 7.0% of TAC controls (P ⫽ .035). The change in adjusted eGFR from randomization to month 12 was superior with EVR ⫹ reduced TAC versus TAC control (difference ⫽ 8.50; 97.5% confidence interval [CI], 3.74 –13.27) mL/min per 1.73 m2; P ⬍ .001 for superiority). Finally, the rates of bacterial and viral infections, including hepatitis C, cytopenias, and hepatic artery thrombosis were not significantly different between the EVR ⫹ reduced TAC and TAC control arms. However, the relative risk of any adverse events leading to drug discontinuation (hazard ratio [HR], 1.82; 95% CI, 1.25–2.66) and serious infections (HR, 1.76; 95% CI, 1.03–3.00) were significantly higher for EVR ⫹ reduced TAC compared with the TAC control group. The authors concluded that EVR facilitated early TAC minimization with comparable efficacy and superior renal function, compared with a standard TAC exposure regimen 12 months after OLT. Comment. Chronic renal failure after OLT is associated with high morbidity, increased hospitalization costs, and high mortality. Data from the pre-MELD era showed an 18% cumulative incidence of posttransplant chronic renal failure at 5 years (N Engl J Med 2003;349:931–940). Since the inception of MELD-based allocation in 2002, the risk of post-OLT ESRD has increased by 15% compared with the pre-MELD era (Am J Transpl 2011;11:2372–2378). In addition to other risk factors, CNI are the major contributor to the risk for CKD after OLT. The relative lack of nephrotoxicity with sirolimus, an mTOR inhibitor, made it an attractive option for OLT recipients after its approval by the US Food and Drug Administration (FDA) in 1999 among renal transplant recipients. However, the 2 black box warnings had dampened the enthusiasm for sirolimus use among OLT recipients. The first black box warning against sirolimus was issued in 2002 based on unpublished data for its use during the immediate post-OLT period owing to the high incidence of hepatic artery thrombosis, increased wound dehiscence, and, more important, decreased patient and graft survivals. The second black box warning in 2009 was for the patients who were converted from CNI to sirolimus ⱖ6 months after OLT secondary to high overall treatment failure rate, high mortality, and insignificant improvement in renal function (Am J Transpl 2012;12:694 –705). EVR, mTOR-1 inhibitor, was approved by the FDA for kidney transplant recipients in 2010. There are growing data on the safety and efficacy of EVR. Two uncontrolled reports described an improvement in renal function after EVR conversion in patients ⱖ4 years out from OLT (Liver Transpl 2011;17:905–913, Liver Transpl 2009;15:1792–1797). Late conversion of CNI to EVR between 12 and 60 months post-OLT in patients with an eGFR of ⬍60 mL/min demonstrated similar rejection rates compared with standard CNI groups. However, there was no difference in the mean change in

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eGFR from baseline to month 6 between EVR (1.0 mL/min) and controls (2.3 mL/min; P ⫽ .46). The adverse events, including hypercholesterolemia and mouth ulcers, were significantly more frequent in the EVR patients (Liver Transpl 2009;15:1262–1269). The data from 2 randomized, controlled studies on conversion to EVR alone or cyclosporine among those who received cyclosporine and prednisone (weaned off by day 35) and basiliximab induction for 10 days as early as week 4 after OLT showed no difference in complications, rejection, or patient survival between the 2 groups (Am J Transpl 2010;10:2252–2262; Am J Transpl 2012;12:1855– 1865). One of these studies showed significantly higher mean eGFR at 1 year in the EVR group (88 vs 60 mL/min control) and significantly lower occurrence of stage ⬎3 CKD (15% vs 52% control). Another randomized study demonstrated no difference in the mean eGFR at 11 months after randomization between the 2 treatments using the Cockcroft-Gault formula However, the use of the MDRD formula showed superiority for EVR (⫺7.8 mL/min; 95% CI, ⫺14.366 to ⫺1.191; P ⫽ .021; Am J Transpl 2012;12:1855–1865). These 2 studies also described increased infections, leukopenia, hyperlipidemia, and more frequent treatment discontinuations in the EVR group. No hepatic artery thrombosis and no excess of wound healing impairment were noted. More recently, the study by De Simone et al demonstrated that the combination of EVR ⫹ reduced TAC is equally efficacious to the TAC control arm in preventing acute cellular rejection (Am J Transpl 2012;12:3008 – 3020). EVR alone was not sufficient to provide adequate immunosuppression to prevent acute cellular rejection. The TAC elimination arm was terminated early because of a significantly high proportion of efficacy failure (tBPAR, graft loss, or death). The episodes of rejection in the EVR alone (TAC elimination) group were clustered around the time when TAC was eliminated. These results validated the previous finding that mTOR inhibition alone without induction therapy and without additional immunosuppressive medication is not feasible as early as 90 days posttransplantation in a largely unselected OLT population (Am J Transpl 2010;10:2252–2262; Am J Transpl 2012;12:1855–1865). Like previous studies of earlier conversion of EVR, this study also showed the superiority of EVR ⫹ reduced TAC to the TAC control regimen in maintaining the eGFR over 1 year. Although these results are exciting, the following points should be taken into consideration about this study before using it in the clinical practice. This is a randomized, controlled study with an open-label design. The open-label design could introduce bias; however, it was required to finely adjust the levels of TAC and EVR in the respective study arms. The baseline mean eGFR in this study was ⬃80 mL/ min, suggesting a bias toward recruiting patients with relatively normal renal function despite the inclusion criteria of ⱖ30 mL/min. This observation also questions the generalizability of an EVR ⫹ reduced TAC regimen among those with lower eGFR (stage 3 or 4 CKD). Although not signifi-

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cant, the baseline mean eGFR was lowest in the TAC control group. There was a very little difference between baseline and month 12 eGFR in all 3 groups using Cockcroft-Gault and Nankivell equations. The authors used eGFR instead of measured creatinine clearance even though MDRD equation estimate eGFR in 62% and 68% of OLT recipients accurately at 3 months and 1 year after OLT compared with the gold standard (iothalamate creatinine clearance; Liver Transpl 2004:10;301–309). The risk of serious infections and any adverse reaction resulting in drug discontinuation were 72% and 86% higher in the EVR ⫹ reduced TAC group compared with the TAC control group. Approximately one quarter of patients discontinued treatment in the EVR ⫹ reduced TAC regimen compared with 14% in the TAC control arm. The authors were not very clear about the definition of serious infections in this paper. The incidence of pneumonia, considered among the serious infections, was similar in both the groups. Hepatitis C infection was also reported as serious infection and it was higher in the EVR ⫹ reduced TAC group compared with the TAC control group. Recurrence of hepatitis C is the universal phenomenon after OLT. It was not very clear whether these patients developed fibrosing cholestatic hepatitis or accelerated progression of hepatitis C. If they developed either of these conditions despite stratification on pre-OLT hepatitis C status, then the safety of EVR-based regimens among the OLT recipients with hepatitis C needs to be studied further. Although this study showed the superiority of EVR in maintaining eGFR among patients with relatively stable eGFR at 1 year, a significantly higher proportion of patients in the EVR ⫹ reduced TAC group (13.4%) developed proteinuria (⬎0.5 g/d) compared with the TAC control group (5.8%). Long-term outcomes of these patients with proteinuria need to be evaluated. Although not significant, 8 and 5 patients in the EVR ⫹ reduced TAC developed acute renal failure compared with 1 and 4, respectively, in the TAC control group. This is the first adequately powered study to evaluate the noninferiority for the primary efficacy end point and secondary renal function end point. This study clearly demonstrated that conversion to the combination of EVR with low-dose TAC is safe in the early post-OLT period and equally efficacious as TAC control in preventing acute cellular rejection. EVR ⫹ reduced TAC was also associated with superior renal function at 12 months after OLT. Despite the available data, EVR is not yet approved for the use in OLT recipients. Therefore, a careful evaluation of risks of serious infections, especially progression of hepatitis C, drug discontinuation owing to adverse effects, as well as risk of proteinuria associated with EVR, should be considered and discussed with the patient before its application in the clinical practice. PRATIMA SHARMA Division of Gastroenterology Department of Internal Medicine University of Michigan Ann Arbor, Michigan

PRANAB Department of Internal University of Ann Arbor,

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BARMAN Medicine Michigan Michigan

Conflicts of interest The authors disclose no conflicts.

COLITIS, MICROBIOTA, AND COLON CANCER: AN INFERNAL TRIANGLE Arthur JC, Perez–Chanona E, Mühlbauer M, et al. Intestinal inflammation targets cancer-inducing activity of the microbiota. Science 2012;338:120 –123. Chronic intestinal inflammation is well established as a risk factor for colorectal cancer (CRC), although the mechanism for this inflammation remains unclear (Oncogene 2010;29:3313–3323). However, there have been numerous experimental studies suggesting that inflammatory cells and their associated mediators form a microenvironment favoring the development of CRC, most likely by enhancing DNA damage in epithelial cells. It has previously been shown in the colitis-susceptible interleukin (IL)10⫺/⫺ mouse strain that intestinal microbial status modulates the development of colitis-associated CRC (PLoSONE 2009;4:e6026). In the current study, Arthur et al conducted a series of experiments to further evaluate the relationship between inflammation, carcinogenesis, and the colonic microbiota in mice (Science 2012;338:120 –123). First, the researchers showed that the luminal microbiota of the IL10⫺/⫺ mice differed from that of wild-type (WT) healthy controls, and found that the colon-specific carcinogen azoxymethane (AOM) had no significant effect on luminal microbial composition or richness, suggesting that inflammation rather than cancer is associated with the microbial shifts. Adherent-invasive Escherichia coli members of the family Enterobacteriaceae have been shown to be associated with human inflammatory bowel disease (IBD) and CRC (Gut Microbes 2010;1:138, Gastroenterology 2004;127:80). In this study, the investigators found that, relative to WT mice, the luminal microbiota of IL10⫺/⫺ mice exhibited an approximately 100fold increase in E coli, with no difference in total bacterial loads; AOM treatment had no effect on E coli abundance. To investigate the causal relationship between commensal E coli and CRC, the researchers administered AOM to germ-free (GF) IL10⫺/⫺ mice mono-associated with the commensal murine adherent-invasive E coli NC101 or the human commensal Enterococcus faecalis OG1RF, both of which cause aggressive colitis in IL10⫺/⫺ mice (Gastroenterology 2005; 128:891). Both groups of mice developed severe colitis, but while 80% of E coli mono-associated mice developed invasive mucinous adenocarcinoma, E faecalis mono-associated mice rarely developed tumors. Levels of colonic cytokines involved in inflammation and carcinogenesis, as well as infiltrating CD3⫹ T cells, F4/ 80⫹ macrophages, and Ly6B.2⫹ monocytes and neutro-