Seventy-six percent (18/25) of the RCTs were considered to be of good methodologic quality according to the Jadad score (≥3). Four trials were double blinded including an adequate description of the method of double blinding. Almost all of the RCTs used intention to treat (ITT) to analyze the data (84%) and a majority adequately described allocation concealment (AC) (76%).
Meta-Analysis of RCTs in Organ Transplantation Comparing an mTOR-I- With a Calcineurin Inhibitor–Based Treatment
Eight prospective randomized multicenter and two single center trials qualified for this analysis (Table 1). All of these trials compared an mTOR-I- versus a CNI-based therapy after renal transplantation. Most of these studies included de novo or early (within the first month) mTOR-I treatment. There were only three trials with delayed introduction of the mTOR-I (3 months (25, 26), 4.5 months (15), and between months 1 to 6 (24) after transplantation). All of these trials used either monoclonal or polyclonal antibodies as induction therapy. SRL was the mTOR-I used in all trials except of the ZEUS trial by Budde et al. (15) where everolimus (EVRL) was used instead.
Taking these 10 trials together, a total of n=3100 patients were included. The combined estimated RR was 2.27 (Table 3) (95% CI, 1.72–3.01), indicating that the risk for CMV events significantly increases (P<0.0001) in patients under CNI treatment compared with patients under m-TOR-I-treatment. The funnel plot did not reveal asymmetry indicating publication bias. Also, the regression test was not significant (P=0.1914). There was no indication of heterogeneity between the studies (I2=0%, Q-Test for heterogeneity: P=0.3319).
Meta-Analysis of RCTs in Organ Transplantation Comparing a Calcineurin Inhibitor–Based Treatment With a Combination of Calcineurin Inhibitors and mTOR-I
Combination of a CNI and an mTOR-I were shown to be very efficient in terms of prevention of acute rejection. However, side effects were aggravated under the combination (i.e., nephrotoxicity after renal transplantation), especially when both drugs were used in nonreduced doses (reviewed in (17)). A combination therapy of a CNI and an mTOR inhibitor was thought to be particularly valuable in heart transplantation. Here, the antiproliferative effect of mTOR inhibitors on smooth muscle cells was assumed to effectively prevent cardiac allograft vasculopathy (30). Consequently, several trials examining the combination therapy of a CNI and an mTOR inhibitor were initiated.
Twelve prospective randomized multicenter and three single center trials have been included in this meta-analysis; n=7,100 patients (Table 2). Patients either received a CNI plus mTOR-I combination or a CNI therapy with antimetabolites as mycophenolic acid or azathioprine. Nine trials were on kidney, four on cardiac, and two on liver transplantation. The combination therapy was started de novo in all except one trial. In the trial by Masetti et al. (24), liver transplant patients received the combination therapy not until day 10. Everolimus was used in six and sirolimus in the remaining nine trials.
Patients treated with CNI alone had a 2.45-fold risk for a CMV event compared with patients treated with a combination of CNI and mTOR-I (Table 4) (RR, 2.45; 95% CI, 1.76–3.41, P<0.0001). There was no indication of publication bias in the funnel plot as indicated by the regression test showing no significance for the asymmetry (P=0.6265). However, heterogeneity between the studies was significant with I2 =63.67% and P=0.0003.
For the ensuing sensitivity analysis, we looked more closely on year of publication, study design, and the mTOR-I. First, we hypothesized that “earlier” trials may have had a greater problem with underreporting. Therefore, we compared the trials before and after 2006. The difference between those two eras was approaching significance (P=0.0556; RR≤2006 = 1.91 [1.30–2.81] vs RR≥2007 = 3.38 [2.17–5.27]. The difference was highly significant when we used the year of publication as continuous variable (P=0.0045). Next, we compared single versus multicenter trials (RR Single Center 1.55 [0.64–3.76] vs RR Multicenter 2.64 [1.84–3.78]; P=0.2758). The reported relative risk was lower in the single center trials. Because of the paucity of the included single center trials (n=3), a statistically significant difference could not be seen. Lastly, we analyzed the anti-CMV effect of the two mTOR-Is, SRL versus EVRL (RR SRL 2.00 [1.31–3.12] RR EVRL 3.12 [1.98–4.92]; P=0.1554). Although the anti-CMV effect under SRL seemed less vs. EVRL there was again no statistically significant difference.
Clinical Evidence for a Protective Anti-CMV Effect of mTOR Inhibitors
This article summarizes the clinical evidence for an anti-CMV effect of mTOR inhibitors after organ transplantation. We have analyzed randomized clinical trials with adequate scientific quality as indicated by the Jadad score and/or adequate allocation concealment and ITT analysis. The first meta-analysis confirmed a solid anti-CMV effect of mTOR-I treatment. The risk to acquire a CMV infection on an mTOR-I was less than half compared with patients on CNI. Corresponding with the “natural” peak of CMV infections after transplantation, the anti-CMV effect seemed most pronounced in the studies using de novo mTOR-Is or very early conversion approaches. When looking specifically at the three trials of our analysis with later conversion time points we found a trend toward a weaker anti-CMV effect. However, the anti-CMV effect was still detectable and statistically significant in a meta-analysis (data not shown). Skewing of the combined relative risk by these late conversion studies was excluded by a meta-regression analysis (data not shown).
Another important question is, whether the proposed anti-CMV effect of mTOR-Is is also evident when used in combination with CNIs. Our meta-analysis clearly suggests that the anti-CMV effect persists in combination with CNIs. The effect seemed unperturbed by the transplanted organ and the intensity of immunosuppression. All but one trial started the immunosuppression with the mTOR-I de novo. Only Masetti et al. (24) used a delayed introduction 10 days after liver transplantation.
The CMV incidence under mTOR-I + CNI treatment ranged from 0% to 10% and was thus unaltered to mTOR-I treatment without CNI of our previous analysis. Because of the significant heterogeneity of the trials, we performed further calculations. First, we hypothesized that “earlier” trials possibly had a greater problem with underreporting of CMV events. In the “early” era, the anti-CMV effect of mTOR-Is and the significance of this finding were not as well established. Indeed, there was a significant difference when the year of publication was used as continuous variable. Of note, none of the included studies were powered to detect differences in CMV incidences. Clinically evident CMV infections were reported as (serious) adverse events, which as a matter of fact leads to significant underreporting of events. Also management of CMV prophylaxis differed. Most trials used prophylaxis exclusively in high-risk patients for 3 months. Only three trials required all patients to use prophylaxis (33, 41, 45). We also looked more specifically at the effect of the different mTOR-Is SRL and EVRL. The anti-CMV effect of EVRL seemed more pronounced compared to SRL (RR SRL 2.00 [1.31 – 3.12] RR EVRL 3.12 [1.98 – 4.92]; P=0.1554). Importantly, EVRL was used preferentially in more recent trials (4/6 appeared after 2006) and SRL in “earlier” trials. Thus, the seemingly stronger anti-CMV effect of EVRL may rather be attributed to the differences reported for “publication year” earlier on. Finally, we speculated that study design might also have had an impact on the reported heterogeneity. When comparing single versus multicenter trials, we saw a reduced RR in the single center trials (RR single center 1.55 [0.64–3.76] vs RR multicenter 2.64 [1.84–3.78]; P=0.2758). A statistically significant difference was not to be expected because of the small number of single center trials included.
These factors together likely have interfered with the heterogeneity seen in our second meta-analysis.
Mechanistic Clues for the Anti-CMV Effect of mTOR Inhibitors
What are the biological mechanisms behind the anti-CMV effect of mTOR inhibitors?
Inhibition of Virus mRNA Translation
Viruses typically rely on the host’s protein synthesis to produce viral mRNA (48). Cytomegalovirus production, for example, needs translation of 7-methyl guanosine (m7G)-capped mRNAs (48). Some viruses have evolved mechanisms to manipulate the translation process of the protein synthesis for which the mTOR kinase is a central molecule. The mTOR-kinase is an activating subunit of mTORC1 and mTORC2. Upon activation, mTORC1 phosphorylates and induces p70S6 kinase, which promotes ribosomal biogenesis (49). At the same time, mTORC1 phosphorylates and inactivates the translational repressor 4EBP1 (49). This protein is thought to have key function for the virus production. Under mTOR-inhibition, 4EBP1 remains hypophosphorylated. It can thus bind the mRNA cap recognition protein eIF4E, preventing the formation of the eIF4F complex and thereby blocking translation (Fig. 2) (50). This could be confirmed when it was shown that inhibition of mTORC1 but not rapamycin-resistant mTORC2 significantly reduces CMV replication (51).
However, the inhibitory effect of the rapamycin is significantly less profound compared with a direct inhibitor of the mTOR kinase (Torin1). It seems that there is rapamycin-sensitive as well as rapamycin-resistant mTORC1. Torin 1 leads to an inhibition of both kinases exerting a more potent antiviral effect compared with the rapamycin that binds to the FK binding protein (FKBP) 12, which in turn binds mTOR, preventing its association with the essential mTORC1 component raptor.
Another explanation for the anti-CMV effect of mTOR-Is may be related to immune modulatory effects, which may lead to an increase in number and quality of antigen-specific CD8+ memory T cells (52). Here, increased numbers of antigen-specific CD8 T cells were seen in both lymphoid and nonlymphoid tissues when mice were infected with lymphocytic choriomeningitis virus (LCMV) and received SRL treatment. Interestingly, numbers of virus-specific CD8 T cells were similar between the SRL and the control group at the peak of the T cell response on d8 after infection. However, the contraction phase of the T cell response (d 8-30) in which usually greater than 90% of the Teff cells disappear and cells undergo effector to memory transition was shown to be minimal under SRL because of decreased apoptosis. Also, markers, which are indicative for functional capacity (CD127, CD62L, and Bcl-2) were upregulated on these virus-specific CD8+ memory T cells under SRL.
Myelomonocytic cells are of particular importance for persistence and spread of the CMV (53, 54). In human macrophages, a sustained mTOR activation was shown to be mandatory for an efficient viral protein synthesis especially during the late phase of the viral cycle (55). Treatment of these cells with an mTOR-I–abrogated CMV replication.
mTOR inhibitors may also stimulate innate immunity. Proinflammatory cytokines as IL-12 and IL-1beta were shown to be up and regulatory cytokines as IL-10 downregulated when treated with an mTOR-I. Furthermore, MHC antigen presentation via autophagy in macrophages and dendritic cells was boosted (reviewed in (56)).
Interestingly, mTOR inhibitors may also reverse some of the unspecific effects of glucocorticoids on innate immunity (57). Under the inhibition of mTOR by SRL, glucocorticoids could no longer inhibit NF-κB and JNK activation in monocytes and myeloid dendritic cells. Furthermore, GCs could not inhibit the expression of proinflammatory cytokines and the promotion of Th1 responses under concurrent SRL therapy (57). Possibly, this conservation of the basic innate immunity function helps to control viral infections.
If and to what extent, however, these mechanisms contribute to the antiviral effect of the mTOR-Is remain to be elucidated.
CMV Prophylaxis or Preemptive Therapy Under mTOR-I Therapy
Primary CMV infections as well as CMV reactivations can occur in transplant recipients. The risk seems especially high for those with primary infections who have not yet encountered the virus (58). The immune system requires a relevant exposure to the virus to mount an efficient immune response, typically during the stage of viremia (59). Therefore, immunity against CMV may be prevented by the prophylactic use of antiviral substances such as (val-)ganciclovir. Several studies show that CMV specific CD4+ and CD8+ T cells are of particular importance for the immunologic response (60, 61). A percentage of ≥0.03% CD4+ T-cells specific for the pp65 was predictive that patients would not develop CMV viremia (62).
A series of trials on prophylaxis versus preemptive therapy highlight the importance of an adequate T-cell response to acquire immunity against CMV. Kliem et al. (10) showed a CMV incidence of 73% (D+R-), 55% (D+ R+), and 24% (D- R+) within 1 year in patients receiving preemptive therapy. Consequent prophylactic therapy was able to reduce CMV infections by 65% overall. However, late-onset CMV infection was found to occur more often after termination of CMV prophylaxis as compared with patients on preemptive therapy. Similar results were shown in another trial by Reischig at al. (63). In this trial, prophylaxis was given for 90 days. In the preemptive therapy group, VGCV treatment was started once CMV DNAemia was greater than 2,000 copies/mL. Although CMV DNA was detectable in virtually all (92%) patients on preemptive therapy, there was no difference in CMV disease (6% vs 9%) up to 12 months after transplantation.
Surprisingly, a systematic review revealed a lower overall incidence for CMV disease under preemptive therapy (2.6%; 10 trials) compared with VGCV prophylaxis (9.9%; 25 trials), without differences regarding rejection or graft loss (13).
Do we have to include mTOR-I into the equation whether to use CMV prophylaxis or preemptive therapy? The data indicate that transplant clinicians have a good tool to effectively reduce CMV related complications with the preemptive as well as prophylactic treatment. Nonetheless, irrespective of the treatment modality up to 20% of the high risk (D+ R-) patients will eventually develop CMV disease (13). Notwithstanding, the efficacy of prophylactic antiviral therapy with (val-)ganciclovir, prophylaxis may prevent effective long-term CMV immunity and is associated with clinically relevant side effects and a significant economic burden. Currently, we have no data to estimate how an mTOR-I based therapy compares with prophylaxis or preemptive therapy with regard to CMV viremia or disease. However, an mTOR-I–based immunosuppression, if started anyway, may be the tipping point toward the use of a preemptive therapy. Especially, because the side-effect profile of (val-)ganciclovir and mTOR-I have some negative overlap on RBC and WBC counts.
These meta-analyses suggest that mTOR-Is have a robust anti-CMV effect, either in combination with antimetabolites or CNIs: in de novo and early conversion regimens but also in late conversion studies. Whether these findings should have implications in patients’ care can only be answered in a prospective trial comparing (val-)ganciclovir-based prophylaxis to a preemptive therapy with an mTOR-I–based immunosuppressive regimen. At this point, however, we believe that a preemptive CMV strategy can be considered safe in patients receiving an mTOR inhibitor–based immunosuppression.
MATERIALS AND METHODS
Identification of the Eligible Trials
Full reports of controlled trials were searched via PubMed (http://www.ncbi.nlm.nih.gov), ScienceDirect (http://www.sciencedirect.com) and the Cochrane Central Register of Controlled Trials (http://www.mrw.interscience.wiley.com/cochrane/cochrane_clcentral_articles_fs.html) up to 3 January 2012 using the optimally sensitive strategies for the identification of eligible trials, combined with the following MeSH terms: “sirolimus,” “rapamycin,” “everolimus,” “Certican,” and “transplantation” (Fig. 1).
Only prospective randomized multicenter or single center studies were included. Retrospective reports and conference abstracts were excluded. A “non-mTOR-I” treatment arm was mandatory. The primary analysis selected those trials, which compared an mTOR-I with a CNI arm. For the second analysis, trials were included, which compared a combination of mTOR-I + CNI with a CNI treatment arm. The retrieved trials were screened for scientific quality and information on CMV infections.
When several publications used the same cohort of patients, only one with the most complete report on CMV was included. No conference abstracts were included.
To summarize the available evidence, we calculated relative risks (RRs) from incidences of CMV infections under CNI- and mTOR-I–based immunosuppression. Publication bias was assessed by plotting study results against precision of the study (funnel plots) and the according regression tests (64). Between study heterogeneity was examined using the Q test for heterogeneity and the I2 statistic (65). Accounting for possible heterogeneity between the studies, we fitted random effects models to derive pooled estimators of the natural logarithms of the RR using the restricted maximum-likelihood estimator (66). Standard errors were estimated using incidences and number of patients per group.
All calculations were performed using the metafor package in the statistical software package R (version 2.13.1).
Data Extraction and Methodologic Quality
The following data were extracted from eligible articles by one reviewer (J.A.): type of transplanted organ, number of patients per treatment arm, induction therapy, mTOR-I dose, start of mTOR-I treatment posttransplantation, trough levels, follow-up period, description and incidence of CMV events, and statistical analysis of the CMV incidence between mTOR-I and CNI treatment.
Methodologic quality was assessed by two reviewers (J.A. and V.H.) using the Jadad score, AC, and ITT analysis (67, 68). The Jadad score addresses the items randomization, blinding, and description of withdrawals and dropouts. The score ranges from 0 to 5, whereas a score of at least 3 is being considered to be consistent with sound methodologic quality. Allocation concealment and intention to treat were included in the overall assessment of quality, according to previously published reports (69).
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Keywords:© 2012 Lippincott Williams & Wilkins, Inc.
mTOR-Inhibitors; Cytomegalovirus; Calcineurininhibitors; Meta-analysis; Systematic review