Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This multicentre RCT investigated the use of Maribavir (a UL97 protein kinase inhibitor) in post-transplant (HCT or SOT) patients with refractory CMV infection. Maribavir was compared to investigator assigned treatment with either valganciclovir/ganciclovir, foscarnet, or cidofovir. CMV clearance was significantly more likely in the Maribavir group (55.7% vs 23.9%) and demonstrated less nephrotoxicity than foscarnet, and less myelosuppression than valganciclovir/ganciclovir. Whilst unblinded, the study is pragmatic and well designed. There is some variability in included patients (“refractory” patients had to have failed to respond to one first line therapy, but this was not specified in detail) and in the investigator assigned comparator group, but this likely reflects real-world variations in practice. The results encouraging for the use of Maribavir as an alternative, potentially less toxic, alternative to existing therapies in this setting.
Expert Review
Reviewer:
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Clinical Impact Rating
4
Review:
Treatment of refractory cytomegalovirus (CMV) infection in solid organ transplant recipients is challenging, with existing therapies limited by toxicity and drug resistance. Ganciclovir resistance is frequently seen, and foscarnet is associated with renal dysfunction in around 50% of patients treated (1). Safer, more effective treatments are needed to improve outcomes. Avery and colleagues have recently reported the outcomes of a multicentre, phase 3 randomised controlled trial of Maribavir, a novel UL97 protein kinase inhibitor that interferes with CMV DNA replication and encapsidation (2). The study randomised solid organ or stem cell transplant recipients with refractory CMV infection to Maribavir or investigator assigned treatment (IAT; valganciclovir/ganciclovir, foscarnet or cidofovir). Maribavir-treated patients demonstrated significantly higher clearance of viraemia after 8 weeks of treatment compared to IAT (55.7% vs. 23.9%). This response also appeared more sustained with Maribavir, with more patients achieving viraemia clearance and symptom control through to week 16. Perhaps as importantly, Maribavir also appeared to have an improved safety profile compared to other agents. Incidence of renal dysfunction was lower than with foscarnet, and neutropenia was less frequent than valganciclovir/ganciclovir. Dysguesia was the most frequently reported side effect in Maribavir-treated patients. Overall, fewer patients discontinued therapy due to side effects than in the IAT group. The study is pragmatic and well designed. It is not blinded, although this would be challenging give n the different routes of administration of the various agents. There is some variability in included patients (“refractory” patients had to have failed to respond to one first line therapy, but this was not specified in detail) and in the investigator assigned comparator group, but this likely reflects real-world variations in practice. Overall, the results are very encouraging and suggest that Maribavir offers an effective, better tolerated alternative to existing therapies for refractory CMV. References 1. Avery RK, Arav-Boger R, Marr KA et al. Outcomes in Transplant Recipients Treated With Foscarnet for Ganciclovir-Resistant or Refractory Cytomegalovirus Infection. Transplantation 2016; 100: e74. 2. Avery RK, Alain S, Alexander BD et al. Maribavir for Refractory Cytomegalovirus Infections With or Without Resistance Post-Transplant: Results from a Phase 3 Randomized Clinical Trial. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America 2021; : ciab988.
Aims:
This study aimed to investigate the safety and efficacy of maribavir compared to investigator-assigned therapy (IAT) for the treatment of with or without resistance cytomegalovirus (R/R CMV) infection in solid-organ transplant (SOT) and hematopoietic-cell transplant (HCT) recipients.
Interventions:
Participants were randomised to either the maribavir group or the IAT group.
Participants:
352 HCT and SOT recipients.
Outcomes:
The primary outcome was confirmed CMV viremia clearance. Secondary outcomes included achievement of CMV clearance and symptom control.
Follow Up:
16 weeks
BACKGROUND:
Therapies for refractory cytomegalovirus infections (with or without resistance [R/R]) in transplant recipients are limited by toxicities. Maribavir has multimodal anti-cytomegalovirus activity through the inhibition of UL97 protein kinase.
METHODS:
In this phase 3, open-label study, hematopoietic-cell and solid-organ transplant recipients with R/R cytomegalovirus were randomized 2:1 to maribavir 400 mg twice daily or investigator-assigned therapy (IAT; valganciclovir/ganciclovir, foscarnet, or cidofovir) for 8 weeks, with 12 weeks of follow-up. The primary endpoint was confirmed cytomegalovirus clearance at end of week 8. The key secondary endpoint was achievement of cytomegalovirus clearance and symptom control at end of week 8, maintained through week 16.
RESULTS:
352 patients were randomized (235 maribavir; 117 IAT). Significantly more patients in the maribavir versus IAT group achieved the primary endpoint (55.7% vs 23.9%; adjusted difference [95% confidence interval (CI)]: 32.8% [22.80-42.74]; P < .001) and key secondary endpoint (18.7% vs 10.3%; adjusted difference [95% CI]: 9.5% [2.02-16.88]; P = .01). Rates of treatment-emergent adverse events (TEAEs) were similar between groups (maribavir, 97.4%; IAT, 91.4%). Maribavir was associated with less acute kidney injury versus foscarnet (8.5% vs 21.3%) and neutropenia versus valganciclovir/ganciclovir (9.4% vs 33.9%). Fewer patients discontinued treatment due to TEAEs with maribavir (13.2%) than IAT (31.9%). One patient per group had fatal treatment-related TEAEs.
CONCLUSIONS:
Maribavir was superior to IAT for cytomegalovirus viremia clearance and viremia clearance plus symptom control maintained post-therapy in transplant recipients with R/R cytomegalovirus. Maribavir had fewer treatment discontinuations due to TEAEs than IAT. Clinical Trials Registration. NCT02931539 (SOLSTICE).
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This donor intervention study randomised 199 deceased brain dead donors to 4 groups – levothyroxine, methylprednisolone, both or control. Primary outcome was the vasoactive inotropic score (VIS), a measure of inotropic requirement at various time points prior to procurement. Both per-protocol and ITT analyses are presented due to relatively high rates of crossover to the combination arm. VIS improved in the methylprednisolone and combination groups, and was worse in the levothyroxine alone group, suggesting that methylprednisolone is the main driver of improved donor stability. Importantly in a donor intervention study, the authors looked at organ utilisation and outcomes following transplantation. These outcomes did not differ significantly between groups, although the study is not powered to these outcomes. These findings are interesting and do question the role of levothyroxine in donor management. The one main caveat is the lack of blinding – this may have increased the crossover rate and impacted inotrope administration, introducing the potential for treatment bias.
Expert Review
Reviewer:
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Clinical Impact Rating
3
Review:
The haemodynamic instability seen in many brain dead (DBD) donors is thought in part to result from disruption in the hypothalamo-pituitary axis, resulting in reduced levels of thyroid hormone and vasopressin (1). For this reason, donor management often includes supplementation of thyroid hormones and vasopressin, and use of corticosteroids. Existing evidence as to the benefits of hormone replacement in the DBD donor is conflicting, with potential benefits of thyroid hormone and desmopressin administration seen in observational registry studies not borne out in prospective randomised controlled trials (2,3). In a recent issue of Transplantation, Van Bakel and colleagues report the results of a prospective randomised controlled trial of donor management in 199 brain-dead organ donors (4). Donors were randomised to four groups: high-dose levothyroxine, high-dose methylprednisolone, combination therapy and no hormonal therapy. Vasopressor requirements were assessed using a validated score (the vasoactive-inotropic score; VIS). The reduction in VIS from baseline was significant in the methylprednisolone and combination groups, but no improvement was seen in the levothyroxine alone or control groups. Unlike many donor intervention studies, the investigators were careful to report organ utilisation and graft outcomes for all groups. No differences were found between groups, although the study was not powered for these outcomes. Of note, the study was not blinded and this may have contributed to significant crossover from other arms to the combination arm and possibly impacted inotrope use. However, the findings above were confirmed in both intent-to-treat and per-protocol analyses. Overall, these results support the existing RCT evidence that thyroid hormone replacement alone does not improve cardiovascular stability in DBD donors, and that the largest impact on stability comes from corticosteroid use. References 1. Howlett TA, Keogh AM, Perry L, Touzel R, Rees LH. Anterior and posterior pituitary function in brain-stem-dead donors. A possible role for hormonal replacement therapy. Transplantation 1989; 47: 828. 2. Macdonald PS, Aneman A, Bhonagiri D et al. A systematic review and meta-analysis of clinical trials of thyroid hormone administration to brain dead potential organ donors. Critical Care Medicine 2012; 40: 1635. 3. Rech TH, Moraes RB, Crispim D, Czepielewski MA, Leitão CB. Management of the brain-dead organ donor: a systematic review and meta-analysis. Transplantation 2013; 95: 966. 4. Van Bakel AB, Hino SA, Welker D et al. Hemodynamic Effects of High-dose Levothyroxine and Methylprednisolone in Brain-dead Potential Organ Donors. Transplantation : 10.1097/TP.0000000000004072
Aims:
The aim of this study was to examine whether high-dose levothyroxine, high-dose methylprednisolone, or a combination of the two hormones, when administered early in the course of donor management, would lead to improvements in donor hemodynamics, allowing significant reduction in vasopressor support.
Interventions:
Participants were randomly assigned to receive high-dose levothyroxine, high-dose methylprednisolone, a combination of both, or no hormonal therapy (control).
Participants:
199 consecutive adult organ donors.
Outcomes:
The primary outcome was the difference in vasopressor requirement to maintain goal hemodynamics among the four treatment groups. Secondary mechanistic outcomes included the assessment of thyroid hormone (TH) levels, cortisol levels and markers of inflammation (C-reactive protein [CRP] and multiple cytokines). Secondary clinical outcomes were the number, types, and proportion of organs procured versus consented, rate of transplantation of procured organs, and patient and graft outcomes of organ recipients exposed to the various treatments.
Follow Up:
120 days
BACKGROUND:
Hormonal replacement therapy is administered to many brain-dead organ donors to improve hemodynamic stability. Previous clinical studies present conflicting results with several randomized studies reporting no benefit.
METHODS:
Consecutive adult donors (N = 199) were randomized to receive high-dose levothyroxine, high-dose methylprednisolone, both (Combo), or no hormonal therapy (Control). Vasopressor requirements using the vasoactive-inotropic score (VIS) were assessed at baseline, 4 h, and at procurement. Crossover to the Combo group was sufficient to require separate intention-to-treat and per-protocol analyses.
RESULTS:
In the intention-to-treat analysis, the mean (±SD) reduction in VIS from baseline to procurement was 1.6 ± 2.6, 14.9 ± 2.6, 10.9 ± 2.6, and 7.1 ± 2.6 for the levothyroxine, methylprednisolone, Combo, and Control groups, respectively. While controlling for the baseline score, the reduction in VIS was significantly greater in the methylprednisolone and Combo groups and significantly less in the levothyroxine group compared with controls. Results were similar in the per-protocol analysis.
CONCLUSIONS:
High-dose methylprednisolone alone or in combination with levothyroxine allowed for significant reduction in vasopressor support in organ donors. Levothyroxine alone offered no advantage in reducing vasopressor support. Organ yield, transplantation rates, and recipient outcomes were not adversely affected.
Dr. Liset Pengel, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
The study tested the hypothesis that reciprocal priming strategies increase organ donor registration intentions and behaviour compared to a control condition. 420 adult participants who were not registered as organ donors from England and Scotland were invited to complete an online survey and were randomised to the reciprocity prime condition or control condition. This sample provided sufficient power to detect a 10% increase in the number of participants who agreed to be taken to the U.K. organ donor registration and information pages. Intention to donate organs was assessed with the statements “I strongly intend to donate my organs when I die” and “I will definitely donate my organs when I die”. Participants in reciprocity prime condition displayed higher intention towards organ donation compared to controls however this did not result in an increase in the number of participants who signed up for organ donor registration. The authors conclude that more research is needed into changing organ donor registration behaviour.
Expert Review
Reviewer:
Prof Jeremy Chapman AC FRACP FRCP, Director of Medicine and Cancer, Westmead Hospital, Sydney, Australia.
Conflicts of Interest:
No
Clinical Impact Rating
1
Review:
Key Findings: This study of organ donation beliefs and, to a certain extent, also actions to commit to organ donation tested a single sentence reminding test subjects of the possibility that they might need an organ transplant (“If you needed an organ transplant would you have one? If so, please help others"). The control group had a bland statement in place of this sentence. Results of this study were that there was a marginal impact on stated intention to donate but no impact on action to increase the chance of donation since there was no impact on the likelihood that particpants would click on the link to the donor registry. It is very hard to see how a single sentence reminding individuals of reciprocal altruism could have a major impact despite the background media along the same lines from the national authority. Generalizability: The main impact is to emphasise again that beliefs and attitudes towards organ donation are strongly held and are not easily modified through community attitudinal modification through marketing approaches. This should encourage agencies seeking to modify attitudes to rely on behavioural modification or organisational systems rather than reciprocal altruism to increase organ donation. Implications for clinical practice: Organ donation activity is not decided on the streets or internet by appeal to reciprocal altruism.
Aims:
To assess if a digital reciprocity prime based on reciprocal altruism can effect intention attitudes to organ donation and organ donor registration.
Interventions:
Participants were randomized 1:1 to receive either a reciprocity prime statement (n=210) or control message (n=210) as part of a digital survey.
Participants:
420 participants (223 females; >18 years; had never previously donated an organ and not registered organ donors).
Outcomes:
After the survey, participants were asked to indicate their organ donation intentions by responding to two statements and whether or not they would like to be taken to an organ donation registration and information page.
Follow Up:
From September – October 2017
BACKGROUND:
Internationally the demand for organ transplants far exceeds the available supply of donated organs.
PURPOSE:
We examine if a digital reciprocity prime based on reciprocal altruism can be used to increase organ donor registration intentions and behavior.
METHODS:
Four hundred twenty participants (223 females) from England and Scotland aged 18+ who were not currently registered organ donors were randomized by block allocation using a 1:1 ratio to receive either a reciprocity prime or control message. After manipulation, they were asked to indicate their organ donation intentions and whether or not they would like to be taken to an organ donation registration and information page.
RESULTS:
In line with our previous work, participants primed with a reciprocity statement reported greater intent to register as an organ donor than controls (using a 7-point Likert scale where higher scores = greater intention; prime mean [SD] = 4.3 [1.6] vs. control mean [SD] = 3.7 [1.4], p ≤ .001, d = 0.4 [95% confidence interval [CI] = 0.21-0.59]). There was again however, no effect on behavior as rates of participants agreeing to receive the donation register web-link were comparable between those primed at 11% (n = 23/210) (95% CI = 7.4-16.0) and controls at 12% (n = 25/210) (95% CI = 8.1-17.1), X2 (1) = 0.09, p = .759.
CONCLUSIONS:
Reciprocal altruism appears useful for increasing intention towards joining the organ donation register. It does not, however, appear to increase organ donor behavior.
This is a nicely done randomised prospective crossover study in stable recipients of simultaneous pancreas and kidney (SPK) transplants who were on Prograf together with mycophenolate and steroids. The patients, of whom there were 21, had stable renal and pancreatic function and were randomised to either continue on Prograf or convert to Advagraf over a period of 12 weeks, and then they converted on a one and one basis to Prograf or Advagraf. There was no change in mycophenolate acid levels and tacrolimus blood levels and mycophenolate acid levels remained unchanged regardless of whether they were on Prograf or Advagraf. Cylex levels as a measure of immune response were unchanged and there were no episodes of rejection during the six month study. The authors conclude that this is sound evidence that it is safe to convert between Prograf and Advagraf on a one-to-one basis without any major impact on pharmacokinetic or pharmacodynamics in SPK recipients.
Expert Review
Reviewer:
Dr Claudio Ponticelli, Past Director Nephrology Division Ospedale Maggiore, Milano, Italy.
Conflicts of Interest:
No
Clinical Impact Rating
2
Review:
This is a randomized, prospective, cross-over study aimed to assess the impact of switching 21 stable pancreas and kidney transplant (P/K) recipients from twice-a-day Prograf to once-a-day Advagraf. No difference in tacrolimus or mycophenolic acid levels was noted. ImmuKnow (Cylex) levels, serum creatinine, and blood sugar levels remained unchanged. Even with a small number of participants, the study showed that converting stable P/K recipients from Prograf to Advagraf (1/1) is safe. However, the study cannot provide information about the possibility of converting patients in the early post-transplant period. More important, one may wonder whether the same results can be obtained by giving the same daily dose of Prograf once a day instead of twice a day. Long-term follow-up of a larger number of patients is also needed to evaluate whether Advagraf can actually improve the adherence to prescriptions and to reduce gastro-intestinal troubles.
Aims:
To examine the effect of conversion from standard tacrolimus (Prograf) to long-acting tacrolimus (Advagraf) in stable simultaneous pancreas-kidney (SPK) recipients.
Interventions:
This was a crossover design and participants were randomised to receive either once a day Advagraf or to continue with twice-daily Prograf for 3 months, and then switch to the other formulation for the next 3 months.
Participants:
21 SPK recipients >1 year post-transplant receiving Prograf twice-daily and mycophenolate mofetil (MMF), with an eGFR >30 mL/min/1.72 m2, stable renal and pancreas allograft function and stable tacrolimus trough levels of 3-10 ng/ mL.
Outcomes:
Measured outcomes included tacrolimus, mycophenolic acid and Cylex CD4 + ATP levels, pancreas and renal function, rejection episodes and side effects.
Follow Up:
6 months
INTRODUCTION:
We assessed the pharmacokinetic and pharmacodynamic impact of converting stable simultaneous pancreas-kidney (SPK) recipients from standard tacrolimus (Prograf) to long-acting tacrolimus (Advagraf).
METHODS:
In a randomized prospective crossover study, stable SPK recipients on Prograf were assigned to Prograf with 1:1 conversion to Advagraf or vice versa. Demographics, tacrolimus, mycophenolic acid levels, and Cylex CD4 + ATP levels were taken at specified intervals in addition to standard blood work.
RESULTS:
Twenty-one patients, who were a minimum of 1 year post-transplant, were entered into the study. No difference in tacrolimus or mycophenolic acid levels was noted between patients who were first assigned to Prograf or Advagraf. Additionally, Cylex levels as well as serum creatinine, lipase, and blood sugar levels were unchanged. There were no episodes of rejection during the 6-month study.
CONCLUSIONS:
It is safe to convert between Prograf and Advagraf 1:1, without major impact on pharmacokinetics or pharmacodynamics in SPK recipients.
This is a rather complicated study in that 46 recipients who had a simultaneous pancreatic kidney transplant were extracted from a larger trial comprising just over 200 recipients of a kidney transplant. The main trial was comparing alemtuzumab with rabbit antithymocye globulin and this analysis gives the long term follow up of patients who had a simultaneous kidney and pancreas transplant. Essentially there was no significant difference in the various outcomes looked at, although there was a trend in most of the outcomes for a better outcome with alemtuzumab. The authors conclude that alemtuzumab appears to be as effective and as safe as rabbit antithymocyte globulin when used for induction in combined kidney and pancreas transplantation and pointed out that alemtuzumab is easier to use being a single infusion and costs less, at least at the time of writing. However I think it is fair to say that the findings can be no more than suggestive at this point in time.
Expert Review
Reviewer:
Professor Philip O'Connell, University of Sydney at Westmead Hospital, Sydney, Australia
Conflicts of Interest:
None
Clinical Impact Rating
3
Review:
Randomised trials in pancreas transplant recipients are few and far between because most centres do small numbers and recruitment has been difficult. So, Stratta et al are to be congratulated for undertaking this study of induction antibody therapy. As the authors point out there are advantages in undertaking immunosuppression trials in pancreas transplant recipients - they are a homogeneous group of patients with relatively high rates of rejection. In this study, patients were randomised to receive either alemtuzemab or rATG. However, what is reported is really a subset analysis of a larger trial in kidney transplant recipients. It was a single centre study, numbers were small and there were uneven numbers of participants in either arm. There were no significant differences in rejection rates, graft survival or patient survival. As the authors point out there were proportionately less rejection and better graft survival in the alemtuzumab arm but there were proportionately more patient deaths also. General recommendations about T cell depleting induction therapy cannot be made on the basis of this study because of concerns about study design and the lack of power to detect meaningful differences. Currently, alemtuzumab is not approved for transplantation and the lack of data showing that it is superior to currently available agents makes it difficult to recommend it. This study highlights the advantages of immunosuppression trial in a cohort of patients with high rejection rates - it may be possible to get meaningful results without unrealistically large recruitment. I hope it is a stimulus to undertake multicentre studies where robust outcomes could be achieved.
Aims:
To investigate the outcomes of alemtuzumab (Alem) versus rabbit anti-thymocyte globulin induction (rATG) in recipients undergoing simultaneous pancreas-kidney transplants (SPKT).
Interventions:
Participants were administered with single dose Alem (30mg intraoperatively over 2 hours) and multiple dose rATG (1.5mg/kg/dose starting intraoperatively) induction in combination with tacrolimus or mycophenolate mofetil and early steroid elimination.
Participants:
46 SPKT recipients.
Outcomes:
The outcomes included patient survival, graft survival, post-operative bleeding, early thrombosis, acute rejection, major infection, cytomegalovirus infection, serum creatinine, glomerular filtration rate, haemoglobin A1c level and C-peptide level.
Follow Up:
Mean 80 months.
BACKGROUND:
The study purpose was to analyze midterm outcomes in a prospective trial of alemtuzumab (Alem) versus rabbit anti-thymocyte globulin (rATG) induction in simultaneous pancreas-kidney transplantation (SPKT).
METHODS:
From February 2005 to October 2008, 46 SPKTs (45 portal-enteric drainage) were prospectively randomized as part of a larger kidney transplant study to receive either single-dose Alem (30 mg intraoperatively) or multiple-dose rATG antibody induction (starting intraoperatively, minimum three doses administered) with tacrolimus/mycophenolate ± steroids.
RESULTS:
Of 222 kidney transplant patients enrolled in the study, 46 received SPKTs; 28 (61%) received Alem and 18 (39%) rATG induction. Follow-up ranged from 67 to 111 months (mean 80 months). There were no significant differences between the two groups in 5 years actual patient (86% Alem vs 89% rATG), kidney (82% Alem vs 61% rATG, p = 0.17) or pancreas (68% Alem vs 56% rATG) graft survival rates. Five years death-censored kidney (92% Alem vs 69% rATG, p = 0.09) and pancreas (76% Alem vs 56% rATG, p = 0.198) graft survival rates were slightly higher in patients receiving Alem. Acute rejection (21% Alem vs 44% rATG, p = 0.12) and major infection (39% Alem vs 67% rATG, p = 0.13) rates were slightly lower in the Alem group; cytomegalovirus infections were significantly lower (0 Alem vs 17% rATG, p = 0.05). The incidence of late acute rejection was low in both groups. There were no differences in early pancreas thrombosis (3.6% Alem vs 11% rATG), postoperative bleeding (11% Alem vs 0 rATG), other surgical complications, readmissions or freedom from steroids between groups. In patients with functioning grafts, 5 years mean serum creatinine (1.4 Alem vs 1.6 mg/dl rATG), calculated abbreviated modification of diet in renal disease glomerular filtration rate (55 Alem vs 52 ml/min/1.73 m(2) rATG), hemoglobin A1c (both 5.4%) and C-peptide (2.6 Alem vs 2.3 ng/ml rATG) levels were similar.
CONCLUSIONS:
Single-dose Alem and multiple-dose rATG induction provide similar midterm patient survival and graft functional outcomes with no major differences in morbidity or resource utilization.
CET Conclusion