Towards tolerance in liver transplantation Toti, L.; Manzia, T.M.; Sensi, B. ...
Baillière's best practice & research. Clinical gastroenterology,
October-December 2021, 2021-10-00, 20211001, Letnik:
54-55
Journal Article
Recenzirano
Life-long immunosuppression has always been considered the key in managing liver graft protection from recipient rejection. However, it is associated with severe adverse effects that lead to ...increased morbidity and mortality, including infections, cardiovascular diseases, kidney failure, metabolic disorders and de novo malignancies.
This explains the great interest that has developed in the concept of tolerance in recent years. The liver, thanks to its marked tolerogenicity, is to be considered a privileged organ: up to 60% of selected patients undergoing liver transplantation could safely withdraw immunosuppression.
•Long-term survival in liver transplant patients is still low: the side effects of immunosuppression are the one main reason for this deficiency.•The liver is immunologically privileged over other organs: for this reason, many studies have been carried out in recent decades to understand the best way to achieve complete tolerance.•Withdrawal of immunosuppression can be safely achieved in up to 40% of selected liver transplant recipients.•There is a need to define valid and safe biomarkers able to predetermine tolerance.
We designed a retrospective case-control study to determine the efficacy and feasibility of everolimus (EVR) combined with low-dose tacrolimus (Tac) ab initio versus standard-dose Tac after liver ...transplantation (LT).
Seventy-one adult LT patients, receiving EVR and low-dose Tac without corticosteroids or induction therapy from postoperative day 1 (EVR group) were compared with a well-matched control group of 61 recipients treated with standard-dose Tac in association with antimetabolite.
Baseline characteristics for the two groups were comparable. The overall patient and graft survival rates were similar (P = .908). Liver function was stable during the follow-up. In the EVR group, biopsy-proven acute rejection occurred in two cases (2.8%), whereas chronic rejection occurred in one (1.4%). The EVR group experienced a better renal function already after 2 weeks (estimated glomerular filtration rate: 89.85 36.46 to 115.3 mL/min/1.73 m2 vs. 68.77 16.11 to 115.42 mL/min/1.73 m2; P = .013), which was also observed after a median time of 27 months (range, 0 to 82 months) from LT (estimated glomerular filtration rate: 80 45 to 118.3 mL/min/1.73 m2 vs. 70.9 45 to 88.4 mL/min/1.73 m2; P = .04). After a median time of 27 months, the EVR group showed lower incidence of arterial hypertension and insulin-dependent diabetes mellitus.
Ab initio EVR-based immunosuppression could be a valid option immediately after surgery in recipients at high-risk for post-LT renal impairment.
•A limited experience of everolimus ab initio regimen post–liver transplantation (LT) is reported.•An everolimus-based regimen reduces long-term calcineurin inhibitor (CNI)–side effects after LT.•Everolimus ab initio has been associated with improved renal function post-LT.•Everolimus ab initio is a valid option in recipients with risk of CNI side effects.
Summary
Long‐term functional outcomes of sofosbuvir‐based antiviral treatment were evaluated in a cohort study involving 16 Italian centres within the international compassionate use programme for ...post‐transplant hepatitis C virus (HCV) recurrence. Seventy‐three patients with cirrhosis (n=52) or fibrosing cholestatic hepatitis (FCH, n=21) received 24‐week sofosbuvir with ribavirin±pegylated interferon or interferon‐free sofosbuvir‐based regimen with daclatasvir/simeprevir+ribavirin. The patients were observed for a median time of 103 (82‐112) weeks. Twelve of 73 (16.4%) died (10 non‐FCH, 2 FCH) and two underwent re‐LT. Sustained virological response was achieved in 46 of 66 (69.7%): 31 of 47 (66%) non‐FCH and 15 of 19 (79%) FCH patients. All relapsers were successfully retreated. Comparing the data of baseline with last follow‐up, MELD and Child‐Turcotte‐Pugh scores improved both in non‐FCH (15.3±6.5 vs 10.5±3.8, P<.0001 and 8.4±2.1 vs 5.7±1.3, P<.0001, respectively) and FCH (17.3±5.9 vs 10.1±2.8, P=.001 and 8.2±1.6 vs 5.5±1, P=.001, respectively). Short‐treatment mortality was higher in patients with baseline MELD≥25 than in those with MELD<25 (42.9% vs 4.8%, P=.011). Long‐term mortality was 53.3% among patients with baseline MELD≥20 and 7.5% among those with MELD<20 (P<.0001). Among deceased patients 75% were Child‐Turcotte‐Pugh class C at baseline, while among survivors 83.9% were class A or B (P<.0001). Direct acting antivirals‐based treatments for severe post‐transplant hepatitis C recurrence, comprising fibrosing cholestatic hepatitis, significantly improve liver function, even without viral clearance and permit an excellent long‐term survival. The setting of severe HCV recurrence may require the identification of “too‐sick‐to‐treat patients” to avoid futile treatments.
First-generation protease-inhibitors (PIs) have suboptimal efficacy in GT-1 patients with advanced liver disease, and patients experiencing treatment failure may require urgent retreatment. Our ...objective was to analyse the real-life efficacy of interferon (IFN)-free retreatment after PI-failure, and the role of genotypic-resistance-testing (GRT) in guiding retreatment choice.
In this multi-centre observational study, patients retreated with IFN-free regimens after first-generation PI-failure (telaprevir-boceprevir-simeprevir) were included. Sustained-virological-response (SVR) was evaluated at week 12 of follow-up. GRT was performed by population-sequencing.
After PI-failure, 121 patients (cirrhotic=86.8%) were retreated following three different strategies: A) with ‘GRT-guided’ regimens (N=18); B) with ‘AASLD/EASL recommended, not GRT-guided’ regimens (N=72); C) with ‘not recommended, not GRT-guided’ regimens (N=31). Overall SVR rate was 91%, but all 18 patients treated with ‘GRT-guided’ regimens reached SVR (100%), despite heterogeneity in treatment duration, use of PI and ribavirin, versus 68/72 patients (94.4%) receiving ‘AASLD/EASL recommended, not GRT-guided’ regimens. SVR was strongly reduced (77.4%) among the 31 patients who received a ‘not recommended, not GRT-guided regimen’ (p <0.01). Among 37 patients retreated with a PI, SVR rate was 89.2% (33/37). Four GT-1a cirrhotic patients failed an option (C) simeprevir-containing treatment; three out of four had a baseline R155K NS3-RAS. All seven patients treated with paritaprevir-containing regimens reached SVR, regardless of treatment duration and performance of a baseline-GRT.
Retreatment of PI-experienced patients can induce maximal SVR rates in real life. Baseline-GRT could help to optimize retreatment strategy, allowing PIs to be reconsidered when chosen after a RASs evaluation.
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