Frederik Haupenthal

Background: Standardised tacrolimus trough-level targets limit individualisation of immunosuppressive therapy in kidney transplant recipients. Torque teno virus (TTV) load reflects the net immunosuppressive state of its host. We evaluated the safety of TTV-guided personalised tacrolimus dosing.Methods: This patient- and assessor-blinded, randomised, controlled, non-inferiority, phase 2 trial (EUCT 2022-500024-30-00) enrolled adult, low-risk kidney allograft recipients across 13 academic centres in Europe and has been completed. Participants were randomised 1:1 at month 4 after transplantation to receive tacrolimus dosing guided by TTV load (active arm) or standard-of-care tacrolimus dosing (control arm) for 9 months. The primary endpoint was a composite of infection, graft rejection or loss, or death. Non-inferiority was defined as an upper limit of the two-sided 95% CI below 10% for the between-group difference in the proportion of patients reaching the primary endpoint (active minus control arm) by the end of follow-up in the modified intention-to-treat population.Findings: Between November 2022 and August 2024, 260 patients were randomised, of whom 256 comprised the modified intention-to-treat population: 128 in the active arm and 128 in the control arm. Median age was 57 years, and 95 (37%) participants were female. The primary endpoint occurred in 45 (35%) participants in the active arm and 48 (38%) in the control arm, corresponding to a between-group difference of –2·3% (95% CI –14·1 to 9·4); the criterion for non-inferiority was met. Secondary endpoints showed lower tacrolimus trough-levels and tacrolimus doses in the active arm than in the control arm. A total of 577 adverse events occurred in the active arm and 509 in the control arm and there were two deaths in each arm.Interpretation: TTV-guided tacrolimus dosing is safe in adult, stable, low-risk kidney allograft recipients during the first year after transplantation and might help to personalise immunosuppression in clinical practice.

Background and hypothesis: Malignancy, driven by the effects of immunosuppression, is a major complication following kidney transplantation. The widespread and non-pathogenic Torque Teno virus (TTV) has emerged as a surrogate of the immune status of its host, with prior studies linking TTV load to insufficient and excessive immunosuppression and thus indirectly to graft rejection and infection. Its relationship to malignancy in kidney transplant recipients is unknown. Methods: This prospective observational single center study evaluated 428 patients who underwent kidney transplantation between 2016 and 2019 at the General Hospital of Vienna, Austria. TTV was measured by quantitative polymerase chain reaction in plasma and the primary outcome was the incidence of the first malignancy during years 2–5 post-transplant. Results: In total, 53 patients developed malignancy (53% cutaneous keratinocyte cancer). The mean log10 TTV load during months 4 to 12 post-transplant (logTTVm4–12) was associated with increased malignancy risk with a hazard ratio (HR) of 1.25 [95% confidence interval (CI) 1.02–1.54] in unadjusted analysis and 1.20 (95% CI 0.97–1.48) after adjustment for age, sex, smoking, and body mass index. In a subgroup, the result remained consistent after additional adjustment for tacrolimus and mycophenolate exposure (HR 1.31, 95% CI 1.03–1.67). Patients with logTTVm4–12 >8, a cut-off we previously proposed to indicate infection risk, had an HR of 2.10 (95% CI 1.22–3.60). Conclusions: These findings suggest that a high TTV load—indicating a state of intense immunosuppression—predicts malignancy after kidney transplantation. Monitoring TTV as a marker of immunosuppression may offer a novel strategy for personalizing immunosuppressive therapy and reducing cancer risk.

Background: After kidney transplantation adherence to immunosuppressive medication is crucial for graft survival and its assessment requires valid measurements. The Basel Assessment of Adherence-to Immunosuppressive Medications Scale (BAASIS) is a validated self-report tool to detect non-adherence, however, its ability to predict clinically relevant outcomes remains to be established. Methods: In this prospective cohort study including 226 consecutive kidney graft recipients transplanted at the Medical University of Vienna between 2018 and 2019 the adherence toward immunosuppressive medication was monitored for 2 years after transplantation. The BAASIS was applied at the first outpatient visit and at months 3, 6, 9, 12, and 24 post-transplant to assess the implementation and persistence phase of adherence. Non-adherence was defined by any positive response to one of the BAASIS-items. The primary endpoint was biopsy-proven allograft rejection defined by the Banff meeting report during a maximum follow-up of 4 years. Results: Of the total study cohort [median age 56 years (IQR 46–63), 75 (33%) female], 125 recipients (55%) reported non-adherence at least once. Self-reported non-adherence increased within the first 3 months from 11% to 31% and remained between 27% and 32% at months 6 to 24 post-transplant. Non-adherent recipients experienced more allograft rejections than adherent patients (24%, n = 30 vs. 7%, n = 7; P < .001) during a median follow-up of 3.7 years (IQR 1.0–4.0). Using a time-dependent Cox regression model, the adjusted hazard ratio for allograft rejection associated with previously reported non-adherence was 2.90 (95% confidence interval (CI) 1.51–5.58; P = .001) accounting for recipient sex, age at transplantation, and history of previous transplantation. Conclusion: Our findings support the clinical value of the BAASIS. Its implementation into routine post-transplant care may facilitate the identification of clinically relevant medication non-adherence, enabling timely interventions.

Background: Technology-mediated medication adherence interventions have proven useful, yet implementation in clinical practice is low. The European Network to Advance Best Practices and Technology on Medication Adherence (ENABLE) European Cooperation in Science and Technology Action (CA19132) online repository of medication adherence technologies (MATechs) aims to provide an open access, searchable knowledge management platform to facilitate innovation and support medication adherence management across health systems. To provide a solid foundation for optimal use and collaboration, the repository requires a shared interdisciplinary terminology. Objective: We consulted stakeholders on their views and level of agreement with the terminology proposed to inform the ENABLE repository structure. Methods: A real-time web-based Delphi study was conducted with stakeholders from 39 countries active in research, clinical practice, patient representation, policy making, and technology development. Participants rated terms and definitions of MATech and of 21 attribute clusters on product and provider information, medication adherence descriptors, and evaluation and implementation. Relevance, clarity, and completeness criteria were rated on 9-point scales, and free-text comments were provided interactively. Participants could reconsider their ratings based on real-time aggregated feedback and revisit the survey throughout the study period. We quantified agreement and process indicators for the complete sample and per stakeholder group and performed content analysis on comments. Consensus was considered reached for ratings with a disagreement index of <1. Median ratings guided decisions on whether attributes were considered mandatory, optional, or not relevant. We used the results to improve the terminology and repository structure. Results: Of 250 stakeholders invited, 117 (46.8%) rated the MATech definition, of whom 83 (70.9%) rated all attributes. Consensus was reached for all items. The definition was considered appropriate and clear (median ratings 7.02, IPR 6.10-7.69, and 7.26, IPR 6.73-7.90, respectively). Most attributes were considered relevant, mandatory, and sufficiently clear to remain unchanged except for ISO certification (considered optional; median relevance rating 6.34, IPR 5.50-7.24) and medication adherence phase, medication adherence measurement, and medication adherence intervention (candidates for optional changes; median clarity ratings 6.07, IPR 4.86-7.17; 6.37, IPR 4.80-6.67; and 5.67, IPR 4.66-6.61, respectively). Subgroup analyses found several attribute clusters considered moderately clear by some stakeholder groups. Results were consistent across stakeholder groups and time, yet response variation was found within some stakeholder groups for selected clusters, suggesting targets for further discussion. Comments highlighted issues for further debate and provided suggestions informing modifications to improve comprehensiveness, relevance, and clarity. Conclusions: By reaching agreement on a comprehensive MATech terminology developed following state-of-the-art methodology, this study represents a key step in the ENABLE initiative to develop an information architecture capable of structuring and facilitating the development and implementation of MATech across Europe. The debates and challenges highlighted in stakeholders’ comments outline a potential road map for further development of the terminology and the ENABLE repository. International Registered Report Identifier (IRRID): RR2-10.1136/bmjopen-2021-059674

BACKGROUND Technology-mediated medication adherence interventions have proven useful, yet implementation in clinical practice is low. The European Network to Advance Best Practices and Technology on Medication Adherence (ENABLE) European Cooperation in Science and Technology Action (CA19132) online repository of medication adherence technologies (MATechs) aims to provide an open access, searchable knowledge management platform to facilitate innovation and support medication adherence management across health systems. To provide a solid foundation for optimal use and collaboration, the repository requires a shared interdisciplinary terminology. OBJECTIVE We consulted stakeholders on their views and level of agreement with the terminology proposed to inform the ENABLE repository structure. METHODS A real-time web-based Delphi study was conducted with stakeholders from 39 countries active in research, clinical practice, patient representation, policy making, and technology development. Participants rated terms and definitions of MATech and of 21 attribute clusters on product and provider information, medication adherence descriptors, and evaluation and implementation. Relevance, clarity, and completeness criteria were rated on 9-point scales, and free-text comments were provided interactively. Participants could reconsider their ratings based on real-time aggregated feedback and revisit the survey throughout the study period. We quantified agreement and process indicators for the complete sample and per stakeholder group and performed content analysis on comments. Consensus was considered reached for ratings with a disagreement index of <1. Median ratings guided decisions on whether attributes were considered mandatory, optional, or not relevant. We used the results to improve the terminology and repository structure. RESULTS Of 250 stakeholders invited, 117 (46.8%) rated the MATech definition, of whom 83 (70.9%) rated all attributes. Consensus was reached for all items. The definition was considered appropriate and clear (median ratings 7.02, IPR 6.10-7.69, and 7.26, IPR 6.73-7.90, respectively). Most attributes were considered relevant, mandatory, and sufficiently clear to remain unchanged except for ISO certification (considered optional; median relevance rating 6.34, IPR 5.50-7.24) and medication adherence phase, medication adherence measurement, and medication adherence intervention (candidates for optional changes; median clarity ratings 6.07, IPR 4.86-7.17; 6.37, IPR 4.80-6.67; and 5.67, IPR 4.66-6.61, respectively). Subgroup analyses found several attribute clusters considered moderately clear by some stakeholder groups. Results were consistent across stakeholder groups and time, yet response variation was found within some stakeholder groups for selected clusters, suggesting targets for further discussion. Comments highlighted issues for further debate and provided suggestions informing modifications to improve comprehensiveness, relevance, and clarity. CONCLUSIONS By reaching agreement on a comprehensive MATech terminology developed following state-of-the-art methodology, this study represents a key step in the ENABLE initiative to develop an information architecture capable of structuring and facilitating the development and implementation of MATech across Europe. The debates and challenges highlighted in stakeholders’ comments outline a potential road map for further development of the terminology and the ENABLE repository. INTERNATIONAL REGISTERED REPORT RR2-10.1136/bmjopen-2021-059674

Torque Teno virus (TTV) is nonpathogenic, highly prevalent, and reflects the immune status of its host. Thus, TTV plasma load was suggested for the guidance of immunosuppression post solid organ transplantation. The present study was designed to determine the kinetics of TTV following changes in calcineurin inhibitor (CNI) dose. A total of 48 adult recipients of a kidney graft transplanted at the Medical University of Vienna between 2018 and 2019 with isolated changes in CNI dose were selected from the prospective TTV‐POET trial. TTV plasma load was quantified by in‐house PCR. At Day 30 following CNI dose adaptation (median 33% of daily dose) no changes in TTV load were noted. However, at Day 60, following CNI dose reduction a lower TTV load of 6.4 log₁₀ c/mL (median; interquartile range [IQR] 4.9–8.1) compared with the baseline of 7.1 log₁₀ c/mL (IQR 5.3–8.9) was noted (p = 0.001); there was also a trend toward a higher TTV load following CNI increase (6.6 log₁₀ c/mL, IQR 4.1–9.7 vs. 5.2 log₁₀ c/mL, IQR 4.5–6.8; p = 0.09). The data suggested that TTV load changes become noticeable only 2 months after CNI dose adaptation, which might be the ideal time point for TTV load monitoring.

Introduction: An online interactive repository of available medication adherence technologies may facilitate their selection and adoption by different stakeholders. Developing a repository is among the main objectives of the European Network to Advance Best practices and technoLogy on medication adherencE (ENABLE) COST Action (CA19132). However, meeting the needs of diverse stakeholders requires careful consideration of the repository structure. Methods and analysis: A real-time online Delphi study by stakeholders from 39 countries with research, practice, policy, patient representation and technology development backgrounds will be conducted. Eleven ENABLE members from 9 European countries formed an interdisciplinary steering committee to develop the repository structure, prepare study protocol and perform it. Definitions of medication adherence technologies and their attributes were developed iteratively through literature review, discussions within the steering committee and ENABLE Action members, following ontology development recommendations. Three domains ( product and provider information (D1), medication adherence descriptors (D2) and evaluation and implementation (D3 )) branching in 13 attribute groups are proposed: product and provider information, target use scenarios, target health conditions, medication regimen, medication adherence management components, monitoring/measurement methods and targets, intervention modes of delivery, target behaviour determinants, behaviour change techniques, intervention providers, intervention settings, quality indicators and implementation indicators . Stakeholders will evaluate the proposed definition and attributes’ relevance, clarity and completeness and have multiple opportunities to reconsider their evaluations based on aggregated feedback in real-time. Data collection will stop when the predetermined response rate will be achieved. We will quantify agreement and perform analyses of process indicators on the whole sample and per stakeholder group. Ethics and dissemination: Ethical approval for the COST ENABLE activities was granted by the Malaga Regional Research Ethics Committee. The Delphi protocol was considered compliant regarding data protection and security by the Data Protection Officer from University of Basel. Findings from the Delphi study will form the basis for the ENABLE repository structure and related activities.