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  • Panayotova GG
  • Lunsford KE
  • Quillin RC
  • Rana A
  • Agopian VG
  • et al.
Hepatology. 2024 May 1;79(5):1033-1047 doi: 10.1097/HEP.0000000000000715.
CET Conclusion
Reviewer: Mr John Fallon, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This large open labelled multi-centre randomised control trial is an exciting development in the field of liver HMP. The key strength of this work is that 43% (n=27) of the HMP-O2 livers had continuous perfusion, having been placed on device at the donor. This is the first trial in liver HMP to do this and is an important development. Made possible by Organ Recovery Systems portable Lifeport Liver device, especially considering 81% travelled by air, a current limitation of the portable NMP devices. They demonstrated a nonsignificant reduction in EAD with 11% in HMP-O2 and 16% in SCS, while the finding is not significant it is in keeping with the 5 other published RCTs on HMP liver. The lack of significance may derive from the fact that within the intervention group only 24% were ECDs (including 5 DCD), upon sub-group analysis of these ECDs they find the reduction of EAD to be significant (20% in HMP-O2 and 33.3% in SCS p=0.004). This is in keeping with previous large RCTs that the beneficial effects of HMP-O2 are amplified in the ECD cohort, especially in DCDs seen in Rijn et al’s 2021 trial published in the New England Journal who perfused only DCD livers. None of their secondary outcomes reach significance, but with PNF only occurring in the SCS group with 3 patients and a further 2 (n=5 6.8%) went on to require re-transplant also due to ischaemic cholangiopathy. In HMP-O2 only 1 required retransplant, this was due to HAT. Biliary complications were nearly double in the SCS group (26.4% vs 12.7%) which is impressive, but again this failed to reach significance. The trends are encouraging, but the lack of significance is disappointing, the trial having not been powered for overall EAD rates. An increase cohort size and a focus on EADs could have led to more dramatic results with potentially significance in many of the outcomes. An interesting note is the preservation fluid used in HMP-O2 was Vasosol, a UW-like solution with the addition of nitric oxide donors and vasodilators, this is the first HMP RCT across all organs to utilise this solution and could, in part be responsible for some of the beneficial trends. Unfortunately, the study was not sufficiently powered to compare continuous HMP-O2 with end-ischaemic HMP-O2 and SCS, the overall storage duration being comparable, but the percentage of that time being perfusion obviously being highest in the continuous group. They demonstrate safety and non-inferior efficacy of a novel portable device, which as it becomes more popular and people become more familiar with placing livers on device at retrieval more data should emerge on continuous HMP-O2, this trial was an important step.
Expert Review
Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Review: This is a very interesting randomised controlled trial in liver transplantation, and an important step in the clinical implementation of a new device (the Lifeport Liver Transporter from Organ Recovery Systems). Hypothermic machine perfusion (HMP) with oxygenation was compared to standard static cold storage prior to transplant. The study was set up as a non-inferiority trial, and hence was smaller than it may have been if designed to demonstrate superiority of one treatment. The non-inferiority design was done specifically to obtain 510(k) device clearance in the USA. Randomisation was stratified for MELD score and DCD status to maintain a distribution between study arms. Primary outcome was Early Allograft Dysfunction (EAD). Approximately 40% of grafts in the HMP arm were put on the pump immediately at retrieval, demonstrating the portability of the device and safety in travel. Statistical analysis of the primary outcome proved non-inferiority of oxygenated HMP, but did not demonstrate superiority either. However, the rate of EAD in the control arm was far better than was expected; in the trial it was only 16%, when 30% had been used for the power calculation. When conducting a subgroup analysis of Extended Criteria Donor (ECD) livers, there was a significant benefit of oxygenated HMP, given the higher baseline risk of 33% EAD with static cold storage in this subgroup. This trial report gives very reassuring information regarding the implementation of oxygenated HMP using this device, its ease of use, portability and safety. The benefit is seen in the ECD livers, and there is the possibility of benefits for standard criteria livers as well (for example PNF and biliary strictures) that may have been statistically significant and more clearly demonstrated in a larger trial
Aims: To assess if HMP-O2 improves liver transplant outcomes compare to cold storage.
Interventions: Livers were randomised to intervention, which was HMP-O2 on the Lifeport Liver Transporter device, perfused with Vasosol, or control, which was static cold storage.
Participants: 179 adult whole liver transplant recipients.
Outcomes: The primary outcome was early allograft dysfunction (EAD) as defined by the Olthoff criteria. Secondary outcome measures were PNF, AKI, graft survival, biliary complications. Vascular complications and death. Additional exploratory outcomes were hospital LOS, ICU LOS, lactate clearance, bleeding, incisional hernia and SAEs.
Follow Up: 12 months
BACKGROUND AND AIMS:

In liver transplantation, cold preservation induces ischemia, resulting in significant reperfusion injury. Hypothermic oxygenated machine perfusion (HMP-O 2 ) has shown benefits compared to static cold storage (SCS) by limiting ischemia-reperfusion injury. This study reports outcomes using a novel portable HMP-O 2 device in the first US randomized control trial.

APPROACH AND RESULTS:

The PILOT trial (NCT03484455) was a multicenter, randomized, open-label, noninferiority trial, with participants randomized to HMP-O 2 or SCS. HMP-O 2 livers were preserved using the Lifeport Liver Transporter and Vasosol perfusion solution. The primary outcome was early allograft dysfunction. Noninferiority margin was 7.5%. From April 3, 2019, to July 12, 2022, 179 patients were randomized to HMP-O 2 (n=90) or SCS (n=89). The per-protocol cohort included 63 HMP-O 2 and 73 SCS. Early allograft dysfunction occurred in 11.1% HMP-O 2 (N=7) and 16.4% SCS (N=12). The risk difference between HMP-O 2 and SCS was -5.33% (one-sided 95% upper confidence limit of 5.81%), establishing noninferiority. The risk of graft failure as predicted by Liver Graft Assessment Following Transplant score at seven days (L-GrAFT 7 ) was lower with HMP-O 2 [median (IQR) 3.4% (2.4-6.5) vs. 4.5% (2.9-9.4), p =0.024]. Primary nonfunction occurred in 2.2% of all SCS (n=3, p =0.10). Biliary strictures occurred in 16.4% SCS (n=12) and 6.3% (n=4) HMP-O 2 ( p =0.18). Nonanastomotic biliary strictures occurred only in SCS (n=4).

CONCLUSIONS:

HMP-O 2 demonstrates safety and noninferior efficacy for liver graft preservation in comparison to SCS. Early allograft failure by L-GrAFT 7 was lower in HMP-O 2 , suggesting improved early clinical function. Recipients of HMP-O 2 livers also demonstrated a lower incidence of primary nonfunction and biliary strictures, although this difference did not reach significance.

  • Schultz BG
  • Bullano M
  • Paratane D
  • Rajagopalan K
Transpl Infect Dis. 2024 Apr;26(2):e14216 doi: 10.1111/tid.14216.
CET Conclusion
Reviewer: Mr Keno Mentor, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: CMV infection which is refractory to standard treatment is a challenging clinical problem, resulting in patient morbidity and increased healthcare costs, mainly due to prolonged and repeat admissions. In the SOLSTICE trail, Maribavir was shown to be more effective than standard treatment protocols for refractory CMV infection in post-transplant patients. This post-hoc analysis of the SOLISTICE trial used trial data to calculate the reduction in healthcare costs that could be achieved by using Maribavir in this patient population. The analysis demonstrated a third to two thirds reduction in costs over an 8-week period when using Maribavir. Healthcare cost analyses are complex and subject to many assumptions, which the authors acknowledge introduces significant bias. However, the most striking omission from the analysis is the cost of the Maribavir treatment itself, which is significantly higher than standard therapy. With the additional limitation of a short duration of study, the reliability and applicability of the reported cost savings cannot be readily determined.
Expert Review
Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Review: This paper represents further work from the SOLSTICE study, published in 2022. This RCT investigated the treatment of refractory CMV in organ transplant and stem cell transplant recipients. In the previous paper, Maribavir was shown to be significantly better at clearing CMV than standard treatment, with less nephrotoxicity than foscarnet and less myelosuppression than valganciclovir/ganciclovir. The current paper focusses on the cost-effectiveness of using Maribavir in this patient group (40% stem cell and 60% solid organ recipients). The potential cost savings are predicated not only on the increased effectiveness of Maribavir, but also on the improved safety profile and reduced complications associated. Clinical data inputs were taken from the SOLSTICE study. Daily costs were derived from the Centers for Medicare and Medicaid Services online price database. Facility-level costs reported by each of the participating facilities in the look-up tool were averaged to yield a representative daily cost. The authors then used annualised mean length of hospital stay for Maribavir and standard treatment groups using length of stay estimates for ICU and non-ICU beds to calculate a mean Per-Patient-Per-Year (PPPY) hospital-care-related cost. The costs presented in the paper do not take into account any difference in the price of Maribavir compared to standard treatments and so should be viewed in that context. The mean PPPY costs of overall hospitalization was lower in the Maribavir group: $67,205 compared to $145,501. From the results of the previous SOLSTICE paper, and the information in this paper, the use of Maribavir in this population is supported in terms of clinical recovery and safety profile. With regards to the cost effectiveness, it is completely possible that any potential reduction in healthcare associated costs is abrogated by a difference in the treatment cost. A weeks’ course of Maribavir currently costs several thousand US dollars. The paper was funded by Takeda pharmaceuticals USA Inc. and both first authors are employees of Takeda Pharmaceuticals USA Inc, with stocks in the company.
Aims: The aim of this study was to use the data from the randomised controlled trial, SOLSTICE, to estimate the cytomegalovirus (CMV) related health care resource utilization (HCRU) costs of maribavir (MBV) versus investigator-assigned therapy (IAT), among hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients.
Interventions: Participants in the SOLSTICE trial were randomised to either receive IAT or MBV therapy.
Participants: 352 patients that had either HSCT (40%) or SOT (60%).
Outcomes: The key outcomes were the cost of hospitalisation with IAT versus MBV therapy, and cost difference (i.e. cost savings) with MBV.
Follow Up: N/A
BACKGROUND:

Cytomegalovirus (CMV) infections among hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients impose a significant health care resource utilization (HCRU)-related economic burden. Maribavir (MBV), a novel anti-viral therapy (AVT), approved by the United States Food and Drug Administration for post-transplant CMV infections refractory (with/without resistance) to conventional AVTs has demonstrated lower hospital length of stay (LOS) versus investigator-assigned therapy (IAT; valgancilovir, ganciclovir, foscarnet, or cidofovir) in a phase 3 trial (SOLSTICE). This study estimated the HCRU costs of MBV versus IAT.

METHODS:

An economic model was developed to estimate HCRU costs for patients treated with MBV or IAT. Mean per-patient-per-year (PPPY) HCRU costs were calculated using (i) annualized mean hospital LOS in SOLSTICE, and (ii) CMV-related direct costs from published literature. Probabilistic sensitivity analysis with Monte-Carlo simulations assessed model robustness.

RESULTS:

Of 352 randomized patients receiving MBV (n = 235) or IAT (n = 117) for 8 weeks in SOLSTICE, 40% had HSCT and 60% had SOT. Mean overall PPPY HCRU costs of overall hospital-LOS were $67,205 (95% confidence interval [CI]: $33,767, $231,275) versus $145,501 (95% CI: $62,064, $589,505) for MBV and IAT groups, respectively. Mean PPPY ICU and non-ICU stay costs were: $32,231 (95% CI: $5,248, $184,524) versus $45,307 (95% CI: $3,957, $481,740) for MBV and IAT groups, and $82,237 (95% CI: $40,397, $156,945) MBV versus $228,329 (95% CI: $94,442, $517,476) for MBV and IAT groups, respectively. MBV demonstrated cost savings in over 99.99% of simulations.

CONCLUSIONS:

This analysis suggests that Mean PPPY HCRU costs were 29%-64% lower with MBV versus other-AVTs.

  • Huang HJ
  • Schechtman K
  • Askar M
  • Bernadt C
  • Mitter B
  • et al.
Transplantation. 2024 Mar 1;108(3):777-786 doi: 10.1097/TP.0000000000004841.
CET Conclusion
Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This pilot study recruited lung transplant recipients at 2 sites, and randomised them to standard immunosuppression (Tac, MMF, Pred) or a belatacept-based regimen (Tac, Belatacept and pred). The hypothesis was that belatacept-based immunosuppression might reduce the incidence of donor-specific antibodies (DSA), leading to a reduction in the risk of chronic lung allograft dysfunction (CLAD). The study was stopped after recruitment of 27 patients due to 3 deaths in the belatacept arm. Causes of death varied – 2 patients died from COVID-19 infection, one from CLAD related to infection, one from PTLD, one from pulmonary embolus and one from haemothorax. The authors ascribe 4 of these deaths to viral infections. No differences were seen in incidence of CLAD or development of DSA. It is very difficult to interpret these results given the small numbers, but clearly the authors were correct in stopping the study and switching patients to standard immunosuppression. The relationship of four of the deaths to viral infection would suggest that the immunosuppressive regimen may have contributed, and in the absence of any detectable clinical benefit, the conclusion that this regimen is unsafe in lung transplant recipients seem justified.
Expert Review
Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Clinical Impact Rating 4
Review: Chronic Lung Allograft Dysfunction (CLAD) is an important long- to medium-term cause of morbidity and mortality following lung transplantation (1). It results predominantly from chronic immune damage, and is associated with the formation of donor-specific antibodies (DSA) (2). Management of CLAD is challenging once established, so most focus is on adequate immunosuppression and prevention of infection to reduce the risk of occurrence (1). Early studies of belatacept, a T-cell co-stimulation blocker, demonstrated a significantly lower incidence of DSA-formation over 7-years post-transplant compared to a calcineurin-inhibitor-based regimen in kidney transplant recipients (3). This led the teams in Houston and St. Louis to design a phase 2 pilot study to investigate the impact of belatacept-based immunosuppression on risk of DSA formation and CLAD in lung transplant recipients, reported in Transplantation recently (4). The study recruited de novo lung transplant recipients, and randomised them to standard immunosuppression (ATG, tacrolimus, mycophenolate and prednisone) or to belatacept-based immunosuppression (tacrolimus, belatacept and prednisone). The study was stopped after recruitment of 27 of patients due to excess mortality in the belatacept arm. Overall, five of 13 patients receiving belatacept died, with one additional death after the end of follow-up. At first glance, causes of death appear varied, with two patients dying of COVID-19, one with CLAD, one post-transplant lymphoproliferative disorder (PTLD), one haemothorax and one pulmonary embolus. However, the authors note that four of 6 deaths had a viral association (viral CLAD, PTLD and COVID-19), with the suggestion that belatacept in this patient population may be associated with increased susceptibility to viral infection and infective complications. It is hard to draw firm conclusions from a small number of patients, but in the absence of any noticeable difference in DSA formation or development of CLAD, this sobering experience would seem to suggest that the risk of de novo belatacept in lung transplant recipients far outweighs any potential theoretical benefit. Other studies have suggested that conversion to belatacept post-transplant might be feasible, but potentially with a higher risk of rejection (5,6). Numbers are small and more evidence is needed before belatacept-based strategies for lung recipients can be recommended. References 1. Gauthier JM, Hachem RR, Kreisel D. Update on Chronic Lung Allograft Dysfunction. Current transplantation reports 2016; 3: 185. 2. Girnita AL, Duquesnoy R, Yousem SA et al. HLA-specific antibodies are risk factors for lymphocytic bronchiolitis and chronic lung allograft dysfunction. American Journal of Transplantation: Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons 2005; 5: 131. 3. Bray RA, Gebel HM, Townsend R et al. De novo donor-specific antibodies in belatacept-treated vs cyclosporine-treated kidney-transplant recipients: Post hoc analyses of the randomized phase III BENEFIT and BENEFIT-EXT studies. American Journal of Transplantation: Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons 2018; 18: 1783. 4. Huang HJ, Schechtman K, Askar M et al. A Pilot Randomized Controlled Trial of De Novo Belatacept-based Immunosuppression After Lung Transplantation. Transplantation 2023; : 10.1097/TP.0000000000004841. 5. Iasella CJ, Winstead RJ, Moore CA et al. Maintenance Belatacept-Based Immunosuppression in Lung Transplantation Recipients Who Failed Calcineurin Inhibitors. Transplantation 2018; 102: 171. 6. Brugière O, Vallée A, Raimbourg Q et al. Conversion to belatacept after lung transplantation: Report of 10 cases. PLOS ONE 2023; 18: e0281492.
Aims: This study aimed to evaluate the feasibility and inform the design of an RCT investigating the efficacy and safety of belatacept following lung transplantation
Interventions: Participants were randomly assigned to either continue standard-of-care immunosuppression or switch to belatacept.
Participants: 27 lung transplant recipients.
Outcomes: The primary outcome was to assess the feasibility of randomising 80% of eligible patients within 4 hours posttransplantation. The primary outcome was later changed to survival following the cessation of treatment with belatacept.
Follow Up: 1 year posttransplantation.
BACKGROUND:

Chronic lung allograft dysfunction (CLAD) is the leading cause of death beyond the first year after lung transplantation. The development of donor-specific antibodies (DSA) is a recognized risk factor for CLAD. Based on experience in kidney transplantation, we hypothesized that belatacept, a selective T-cell costimulatory blocker, would reduce the incidence of DSA after lung transplantation, which may ameliorate the risk of CLAD.

METHODS:

We conducted a pilot randomized controlled trial (RCT) at 2 sites to assess the feasibility and inform the design of a large-scale RCT. All participants were treated with rabbit antithymocyte globulin for induction immunosuppression. Participants in the control arm were treated with tacrolimus, mycophenolate mofetil, and prednisone, and participants in the belatacept arm were treated with tacrolimus, belatacept, and prednisone through day 89 after transplant then converted to belatacept, mycophenolate mofetil, and prednisone for the remainder of year 1.

RESULTS:

After randomizing 27 participants, 3 in the belatacept arm died compared with none in the control arm. As a result, we stopped enrollment and treatment with belatacept, and all participants were treated with standard-of-care immunosuppression. Overall, 6 participants in the belatacept arm died compared with none in the control arm (log rank P  = 0.008). We did not observe any differences in the incidence of DSA, acute cellular rejection, antibody-mediated rejection, CLAD, or infections between the 2 groups.

CONCLUSIONS:

We conclude that the investigational regimen used in this pilot RCT is associated with increased mortality after lung transplantation.