Abstract
Objective: This scoping review aims at systematically mapping reported prognostic factors for spontaneous immunosuppression (IS) free allograft tolerance (operational tolerance, OT) in non-viral hepatitis and non-autoimmune disease liver transplant (LT) recipients who are undergoing immunosuppression withdrawal (ISW). The results may inform the subsequent conduct of a systematic review with a more specific review question. Background: LT is currently the most effective treatment for end-stage liver diseases. Whereas the short-term outcomes after LT have dramatically improved over the last decades, the long-term outcomes remain unsatisfactory, mainly because of side effects of lifelong IS, such as infections, cardiovascular diseases, malignancies, and nephrotoxicity. ISW studies have shown that OT can be achieved by a subset of LT recipients and recent research has identified biomarkers of OT in these patients. However, an evidence-based selection algorithm for patients that can predictably benefit from ISW is not available to date. The planned review will, therefore, map existing knowledge on prognostic clinical parameters and biomarkers for OT. Inclusion criteria: We will consider studies that record any clinical parameter or biomarker before the initiation of ISW in paediatric or adult non-viral hepatitis and non-autoimmune disease LT recipients and analyse their possible association with ISW outcomes (OT or non-tolerance). Studies addressing the effectiveness of OT-inducing treatments will be excluded. Methods: Embase, MEDLINE, and Cochrane Library will be searched for relevant articles or conference abstracts. Full-texts of selected abstracts will be independently screened for inclusion by two reviewers. References and citing articles of included records will be screened for additional relevant records. Clinical trial registries will be searched for ongoing studies, and their investigators contacted for the sharing of unpublished data. Data from included records will be independently extracted by two reviewers using a prespecified data extraction table and presented in both tabular and narrative form.
Highlights
The authors identified a single ongoing randomized controlled trials (RCTs), which has been published in the meantime[47]. In this RCT, the non-inferiority analysis of immunosuppression withdrawal (ISW) vs. unchanged IS maintenance treatment on a composite morbidity/mortality endpoint was inconclusive. Based on these results and an unpublished scoping search in the literature that did not identify any new RCTs on this comparison, we concluded that there was not enough data for a new systematic review approach comparing ISW and IS continuation after liver transplant (LT)
Two ongoing multicenter trials (LIFT51 and OPTIMAL52) share the same inclusion/exclusion criteria. These ISW trials have in parallel fuelled the need to find reliable biomarkers for the identification of those patients who are more likely to successfully stop IS, a problem that is most critical for the safety and future applicability of ISW
While clinically not available yet, several biomarkers have already been evaluated in LT recipients
Summary
MEDLINE, and Cochrane Library will be searched for relevant articles or conference abstracts. Human leukocyte antigen (HLA) match requirements between donor and recipient are less stringent, and the incidence and severity of acute cellular rejection (ACR) episodes are lower and usually better tolerated in LT as compared to other SOT recipients[24] Based on these particular features, clinical studies that examined IS minimization or even complete IS withdrawal (ISW) in LT recipients have been initiated already in the 1990s25–28. In this RCT, the non-inferiority analysis of ISW vs unchanged IS maintenance treatment on a composite morbidity/mortality endpoint was inconclusive Based on these results and an unpublished scoping search in the literature that did not identify any new RCTs on this comparison, we concluded that there was not enough data for a new systematic review approach comparing ISW and IS continuation after LT. Current study status: preliminary searches, yes; piloting of the study selection process, yes; formal screening of search results against eligibility criteria, started; data extraction, no; data analysis, no
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