The improving Medication Adherence in Adolescents and young adults following Liver Transplantation (iMALT) multisite trial: Design and trial implementation considerations

Article

Author: Duncan-Park, Sarah ; Annunziato, Rachel ; Shneider, Benjamin L ; Shemesh, Eyal ; Reyes-Mugica, Miguel ; Mitchell, Jeff ; Mazariegos, George ; Anand, Ravinder

Background/aims Medication non-adherence is a leading cause of transplant rejection, organ loss, and death; yet no rigorous controlled study to date has shown compelling clinical benefits from an adherence-improving intervention. Non-adherent patients are less likely to participate in trials, and therefore, most studies enroll a majority of adherent patients who do not stand to benefit from the intervention, as they do not have the condition (non-adherence) under investigation. The improving Medication Adherence in adolescent Liver Transplant recipients trial specifically targets non-adherent patients to investigate whether a remote intervention to improve adherence results in reduced incidence of biopsy-confirmed rejection. Methods Improving Medication Adherence in adolescent Liver Transplant is a randomized single-blind controlled multisite, multinational National Institutes of Health-funded trial involving 13 pediatric transplant centers in the United States and Canada. An innovative, objective adherence biomarker—the Medication Level Variability Index, which is the standard deviation of a series of medication blood levels for each patient, is used to identify non-adherent patients at risk for rejection. The index is computed using electronic health record information for all potentially eligible patients based on repeated reviews of the entire clinic’s roster. Identified patients, after consent, are randomized to intervention versus control (treatment as usual) arms. The remote intervention is delivered for 2 years by trained interventionists who reside in various locations in the United States. The primary outcome is the incidence of biopsy-confirmed acute cellular rejection, as confirmed by a majority vote of three pathologists who are masked to the study allocation and clinical information. Discussion Improving Medication Adherence in adolescent Liver Transplant includes several innovative design elements. The use of a validated, objective adherence index to survey a large cohort of transplant recipients allows the teams to avoid bias inherent in both convenience sampling and referral-based recruitment and enroll only patients whose computed index indicates substantially increased risk of rejection. The remote intervention paradigm helps to engage patients who are by definition hard to engage. The use of an objective, masked medical (rather than behavioral) outcome measure reduces the likelihood of biases related to clinical information and ensures broad acceptance by the field. Finally, monitoring for potential adverse events related to increased medication exposure due to the adherence intervention acknowledges that a successful intervention (increasing adherence) could have detrimental side effects via increased exposure to and potential toxicity of the medication. Such monitoring is almost never attempted in clinical trials evaluating adherence interventions.

01 May 2022·American Journal of Transplantation

Predictors of survival following liver transplantation for pediatric hepatoblastoma and hepatocellular carcinoma: Experience from the Society of Pediatric Liver Transplantation (SPLIT)

Article

Author: Superina, Riccardo ; Leung, Daniel H ; Martin, Abigail E ; Tiao, Gregory M ; Lovell, Mark A ; Greffe, Brian S ; Stoll, Janis M ; Mazariegos, George V ; Elisofon, Scott A ; Desai, Dev M ; Daniel, James F ; Amin, Arpit ; Roach, Jonathan P ; Anand, Ravinder ; McDiarmid, Suzanne V ; Sundaram, Shikha S ; Lemoine, Caroline ; Sayed, Blayne A ; Vitola, Bernadette E ; Boster, Julia M ; Lobritto, Steven J ; Yanni, George ; Gupta, Nitika A ; Anderson, Sarah G

Management of unresectable pediatric hepatoblastoma (HB) and hepatocellular carcinoma (HCC) remains challenging. The Society of Pediatric Liver Transplantation (SPLIT) database was used to study survival predictors in pediatric liver transplantation (LT) for HB and HCC. Event-free survival (EFS), associated risk factors, and postoperative complications were studied in children requiring LT for HB/HCC at 16 SPLIT centers. Three-year EFS was 81% for HB (n = 157) and 62% for HCC (n = 18) transplants. Of HB transplants, 6.9% were PRETEXT II and 15.3% were POST-TEXT I/II. Tumor extent did not impact survival (p = NS). Salvage (n = 13) and primary HB transplants had similar 3-year EFS (62% versus 78%, p = NS). Among HCC transplants, 3-year EFS was poorer in older patients (38% in ≥8-year-olds vs 86% <8-year-olds) and those with larger tumors (48% for those beyond versus 83% within Milan criteria, p = NS). Risk of infection (HR 1.5, 95% CI 1.1-2.2, p = .02) and renal injury (HR 2.4, 95% CI 1.7-3.3, p < .001) were higher in malignant versus nonmalignant LT. Survival is favorable for pediatric HB and HCC LT, including outcomes after salvage transplant. Unexpected numbers of LTs occurred in PRE/POST-TEXT I/II tumors. Judicious patient selection is critical to distinguish tumors that are potentially resectable; simultaneously, we must advocate for patients with unresectable malignancies to receive organs.

Nature Communications

Neutralizing antibody immune correlates in COVAIL trial recipients of an mRNA second COVID-19 vaccine boost

Article

Author: Winokur, Patricia L ; Gilbert, Peter B ; Chen, Shiyu ; Falsey, Ann R ; Molitor, Cindy ; Wang, Jing ; Mahgoub, Siham M ; Kamidani, Satoshi ; Bäcker, Martín ; Zhang, Bo ; Immergluck, Lilly C ; Branche, Angela R ; Fong, Youyi ; Diemert, David J ; Magaret, Craig A ; Fusco, Dahlene N ; Netzl, Antonia ; Busch, Sydney ; Roberts, Paul C ; Baden, Lindsey R ; Goepfert, Paul A ; Fintzi, Jonathan ; Jackson, Lisa A ; Little, Susan J ; Rouphael, Nadine G ; Presti, Rachel M ; Rupp, Richard ; Makowski, Mat ; Borate, Bhavesh ; Babu, Tara M ; Dang, Lauren ; Mu, Jinjian ; Luetkemeyer, Anne F ; Graciaa, Daniel S ; Novak, Richard M ; Makhene, Mamodikoe K ; Posavad, Christine M ; Whitaker, Jennifer A ; Smith, Derek J ; Yu, Chenchen ; Kottkamp, Angelica C ; Atmar, Robert L ; Nayak, Seema U ; Follmann, Dean ; Benkeser, David ; Walter, Emmanuel B ; Frey, Sharon E

AbstractNeutralizing antibody titer has been a surrogate endpoint for guiding COVID-19 vaccine approval and use, although the pandemic’s evolution and the introduction of variant-adapted vaccine boosters raise questions as to this surrogate’s contemporary performance. For 985 recipients of an mRNA second bivalent or monovalent booster containing various Spike inserts [Prototype (Ancestral), Beta, Delta, and/or Omicron BA.1 or BA.4/5] in the COVAIL trial (NCT05289037), titers against 5 strains were assessed as correlates of risk of symptomatic COVID-19 (“COVID-19”) and as correlates of relative (Pfizer-BioNTech Omicron vs. Prototype) booster protection against COVID-19 over 6 months of follow-up during the BA.2-BA.5 Omicron-dominant period. Consistently across the Moderna and Pfizer-BioNTech vaccine platforms and across all variant Spike inserts assessed, both peak and exposure-proximal (“predicted-at-exposure”) titers correlated with lower Omicron COVID-19 risk in individuals previously infected with SARS-CoV-2, albeit significantly less so in naïve individuals [e.g., exposure-proximal hazard ratio per 10-fold increase in BA.1 titer 0.74 (95% CI 0.59, 0.94) for naïve vs. 0.41 (95% CI 0.23, 0.64) for non-naïve; interaction p = 0.013]. Neutralizing antibody titer was a strong inverse correlate of Omicron COVID-19 in non-naïve individuals and a weaker correlate in naïve individuals, posing questions about how prior infection alters the neutralization correlate.

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