Electronic health record-enabled routine assessment of medication adherence after solid organ transplantation: the time is now.

Medication nonadherence after solid organ transplantation is recognized as an important impediment to long-term graft survival. Yet, assessment of adherence is often not part of routine care. In this Personal Viewpoint, we call for the transplant community to consider implementing a systematic process to screen and assess medication adherence. We believe acceptable tools are available to support integrating adherence assessments into the electronic health record. Creating a standard assessment can be done efficiently and cost-effectively if we come together as a community. More importantly, such monitoring can improve outcomes and strengthen provider-patient relationships. We further discuss the practical challenges and potential rebuttals to our position.

The measure of impact: Proposal of quality metrics for solid organ transplant pharmacy practice.

As healthcare continues its transition toward value-based care, it is increasingly important for transplant pharmacists to demonstrate their impact on patient care, health-related outcomes, and healthcare costs. Evidence-based quality and performance metrics are recognized as crucial tools for measuring the value of service. Yet, there is a lack of well-developed and agreed-upon specific metrics for many clinical pharmacy specialties, including solid organ transplantation. To address this need, a panel of transplant pharmacy specialists conducted a detailed literature review and engaged in several panel discussions to identify quality metrics to be considered for assessing the value of clinical pharmacy services provided to solid organ transplant recipients and living donors. The proposed metrics are based on the Donabedian model and are categorized to coincide with the typical phases of transplant care. The measures focus on key issues that arise in transplant recipients related to medication therapy, including adverse drug events, nonadherence, and clinical outcomes attributable to medication therapy management. This article proposes a comprehensive set of measures, any number of which transplant pharmacists can adopt and measure over time to objectively gauge the value of services they are providing to transplant recipients, the transplant center, and the overall healthcare system.

Expanding the Donor Pool: First Use of Hepatitis B Virus Nat Positive Solid Organ Allografts Into Seronegative Recipients.

OBJECTIVES: The aim of this study was to assess the 1-year safety and effectiveness of HBV Nucleic Acid Test positive (HBV NAT+) allografts in seronegative kidney transplant (KT) and liver transplant (LT) recipients. SUMMARY BACKGROUND DATA: Despite an ongoing organ shortage, the utilization of HBV NAT+ allografts into seronegative recipients has not been investigated. METHODS: From January 2017 to October 2020, a prospective cohort study was conducted among consecutive KT and LT recipients at a single institution. Primary endpoints were post-transplant HBV viremia, graft and patient survival. RESULTS: With median follow-up of 1-year, there were no HBV-related complications in the 89 HBV NAT+ recipients. Only 9 of 56 KTs (16.1%) and 9 of 33 LTs (27.3%) experienced post-transplant HBV viremia at a median of 185 (KT) and 269 (LT) days postoperatively. Overall, viremic episodes resolved to undetected HBV DNA after a median of 80 days of entecavir therapy in 16 of 18 recipients. Presently, 100% of KT recipients and 93.9% of LT recipients are HBV NAT- with median follow-up of 13 months, whereas 0 KT and 8 LT (24.2%) recipients are HBV surface antigen positive indicating chronic infection. KT and LT patient and allograft survival were not different between HBV NAT+ and HBV NAT- recipients (P > 0.05), whereas HBV NAT+ KT recipients had decreased waitlist time and pretransplant duration on dialysis (P < 0.01). CONCLUSIONS: This is the largest series describing the transplantation of HBV NAT+ kidney and liver allografts into HBV seronegative recipients without chronic HBV viremia or decreased 1-year patient and graft survival. Increasing the utilization of HBV NAT+ organs in nonviremic recipients can play a role in decreasing the national organ shortage.

Safety and Efficacy of Budesonide for Liver Transplant Immune Suppression: Results of a Pilot Phase 2a Trial.

Despite adverse effects like hyperglycemia, new-onset diabetes after transplant (NODAT), and infectious complications, corticosteroid use remains an important part of liver transplantation (LT) immune suppression. Budesonide, a synthetic corticosteroid, undergoes extensive first-pass hepatic metabolism with only 10% systemic bioavailability, providing an opportunity for an improved toxicity-therapeutic ratio. Although effective in the treatment of autoimmune hepatitis, the effects of budesonide for LT immune suppression are unknown. We conducted a single-center phase 2a trial to study the safety and efficacy of budesonide immunosuppressive therapy. From July 2017 to November 2018, 20 patients undergoing a first LT received budesonide tapering doses (from 9 to 3 mg) for 12 weeks. Patients were compared with matched control patients who received prednisone from the same time period. Additionally, both groups received calcineurin inhibitors and mycophenolate mofetil. Outcome measures at week 24 included rates of biopsy-proven acute cellular rejection (ACR), NODAT (hemoglobin A1c >6.4%), and infectious complications. In the budesonide arm, 1 patient developed ACR at week 5 and was removed from the study. Another patient stopped the study drug at week 8 due to persistent nausea. Rates of ACR were similar between the budesonide and control groups (5% versus 5%, P = 1.00). Three patients in the control group developed NODAT versus none in the budesonide group (15% versus 0%; P = 0.23). There were 6 infections in the control group compared with none in the budesonide group (30% versus 0; P = 0.02). These pilot data suggest that budesonide has the potential to be a safe and effective alternative to prednisone for LT immune suppression while reducing steroid-induced infections and NODAT. Randomized controlled trials are required to validate these findings.

Use of Hepatitis C Nucleic Acid Test-Positive Liver Allografts in Hepatitis C Virus Seronegative Recipients.

Because of underutilization of liver allografts, our center previously showed that hepatitis C virus (HCV) antibody-positive/nucleic acid test (NAT)-negative livers when transplanted into HCV nonviremic recipients were safe with a 10% risk of HCV transmission. Herein, we present our single-center prospective experience of using HCV NAT+ liver allografts transplanted into HCV NAT- recipients. An institutional review board-approved matched cohort study was conducted examining post- liver transplantation (LT) outcomes of HCV- patients who received HCV NAT+ organs (treatment group) compared with matched recipients with HCV NAT- organs (matched comparator group) between June 2018 to October 2019. The primary endpoint was success of HCV treatment and elimination of HCV infection. The secondary outcomes included the 30-day and 1-year graft and patient survival as well as perioperative complications. There were 32 recipients enrolled into each group. Because of 1 death in the index admission, 30/31 patients (97%) were given HCV treatment at a median starting time of 47 days (18-140 days) after LT. A total of 19 (63%) patients achieved sustained virological response at week 12 (SVR12). Another 6 patients achieved end-of-treatment response, while 5 remained on therapy and 1 is yet to start treatment. No HCV treatment failure has been noted. There were no differences in 30-day and 1-year graft and patient survival, length of hospital stay, biliary or vascular complications, or cytomegalovirus viremia between the 2 groups. In this interim analysis of a matched cohort study, which is the first and largest study to date, the patients who received the HCV NAT+ organs had similar outcomes regarding graft function, patient survival, and post-LT complications.

Alternatives to immediate release tacrolimus in solid organ transplant recipients: When the gold standard is in short supply.

Given the current climate of drug shortages in the United States, this review summarizes available comparative literature on the use of alternative immunosuppressive agents in adult solid organ transplant recipients including kidney, pancreas, liver, lung, and heart, when immediate-release tacrolimus (IR-TAC) is not available. Alternative options explored include extended-release tacrolimus (ER-TAC) formulations, cyclosporine, belatacept, mammalian target of rapamycin inhibitors, and novel uses of induction therapy for maintenance immunosuppression. Of available alternatives, only ER-TAC formulations are of non-inferior efficacy compared to IR-TAC when used de novo or after conversion in stable kidney transplant recipients (KTRs). All other alternatives were associated with higher rates of biopsy-proven rejection, but improved tolerance from classic adverse effects of IR-TAC including nephrotoxicity and development of diabetes. While most alternative therapies are approved in KTRs, access via third-party payors is an obstacle in non-KTRs. In the setting of IR-TAC shortage, alternate therapeutic options may be plausible depending on the organ population and individual patient situation to ensure appropriate, effective immunosuppression for each patient.

Telemedicine Based Remote Home Monitoring After Liver Transplantation: Results of a Randomized Prospective Trial.

OBJECTIVE: This study assesses the impact of a telemedicine-based home management program (THMP) on patient adherence, hospital readmissions, and quality of life (QOL) after liver transplantation (LT). SUMMARY OF BACKGROUND DATA: Telemedicine interventions represent an opportunity to personalize care and can lead to improved adherence and patient satisfaction. However, there is limited data on impact of these interventions on outcomes after LT. Therefore, we conducted the first randomized controlled trial (RCT) of a THMP compared to standard of care (SOC) after LT. METHODS: One hundred six consecutive LT recipients were randomized (1:1) to 1 of 2 posttransplant care strategies: SOC or THMP. The THMP included an electronic tablet and bluetooth devices to support daily text messages, education videos, and video FaceTime capability; data was cyber-delivered into our electronic medical record daily. Endpoints were THMP participation, 90-day hospital readmission rate, and QOL. RESULTS: One hundred patients completed the study with 50 enrolled in each arm. Participation and adherence with telemedicine was 86% for basic health sessions (vital sign recording), but only 45% for using messaging or FaceTime. The THMP group had a lower 90-day readmission rate compared to SOC (28% vs 58%; P = 0.004). The THMP cohort also showed improved QOL in regards to physical function (P = 0.02) and general health (P = 0.05) at 90 days. CONCLUSIONS: To our knowledge, this is the first RCT demonstrating the impact of THMP after LT. The magnitude of effect on LT outcomes, hospital readmissions, and QOL suggests that the adoption of telemedicine has great potential for other major operations.

Delayed Sleeve Gastrectomy Following Liver Transplantation: A 5-Year Experience.

Obesity has become an epidemic in the United States over the past decade, and recent studies have shown this trend in the liver transplantation (LT) population. These patients may be candidates for laparoscopic sleeve gastrectomy (LSG) to promote significant and sustained weight loss to prevent recurrence of nonalcoholic steatohepatitis. However, safety remains a concern, and efficacy in this setting is uncertain. A single-institution database from 2014 to 2018 was queried for patients undergoing LSG following LT. The selection criteria for surgery were consistent with National Institutes of Health guidelines, and patients were at least 6 months after LT. A total of 15 patients (median age, 59.0 years; Caucasian, 86.7%; and female, 60%) underwent LSG following LT. Median time from LT to LSG was 2.2 years with a median follow-up period of 2.6 years. The median hospital length of stay (LOS) was 2 days after LSG. Mortality and rate of liver allograft rejection was 0, and there was 1 postoperative complication (a surgical site infection). Following LSG, body mass index (BMI) decreased from 42.7 to 35.9 kg/m2 (P < 0.01), and in 12 patients with at least 1 year of follow-up, the total body weight loss was 20.6%. Following LSG in patients with diabetes, the median daily insulin requirements decreased from 98 (49-118) to 0 (0-29) units/day (P = 0.02), and 60% discontinued insulin. Post-LT patients had a similar decrease in BMI and reduction in comorbidities at 1 year compared with a matched non-LT patient cohort. In the largest patient series to date, we show that LSG following LT is safe, effective, and does not increase the incidence of liver allograft rejection. Larger longer-term studies are needed to confirm underlying metabolic changes following LSG.

Use of HCV Ab+/NAT- donors in HCV naïve renal transplant recipients to expand the kidney donor pool.

Hepatitis C (HCV) disease transmission from the use of HCV antibody-positive and HCV nucleic acid test-negative (HCV Ab+/NAT-) kidneys have been anecdotally reported to be absent. We prospectively analyzed kidney transplant (KT) outcomes from HCV Ab+/NAT- donors to HCV naïve recipients under T-cell depleting early steroid withdrawal immunosuppression. Allografts from 40 HCV Ab+/NAT- donors were transplanted to 52 HCV Ab- recipients between July 2016 and February 2018. Thirty-three (82.5%) of donors met Public Health Service (PHS) increased risk criteria. De novo HCV infection was detected at 3 months post-KT in one recipient (1.9%). This was a case of transmission from a HCV Ab+ NAT+ donor with an initial false-negative NAT completed using sample collected on donor hospital admission (day 2). At the time of HCV diagnosis, a stored donor sample collected during procurement (day 4) was tested and resulted NAT-positive. Subsequently, sustained virologic response (SVR) was achieved with 12 weeks of glecaprevir/pibrentasvir. One death with functioning graft at 261 days post-KT was determined not related to HCV or donor factors. This experience provides evidence of a low transmission rate of HCV from HCV Ab+/ NAT- kidney donors, thereby arguing for increasing utilization.

Meeting report: Consensus recommendations for a research agenda to address immunosuppressant nonadherence in organ transplantation.

Despite advances in the field of transplantation, immunosuppressant medication nonadherence (NA) remains a primary contributor to suboptimal long-term outcomes. Due to the multidimensional and multifactorial causes of medication NA, studies to date have focused on individual differing facets or single point barriers of NA with relative success. However, these successes have not proven to be sustainable, partly due to the intense resources needed for continued viability. This article provides a summary of a 2-day meeting held in April 2017 (Chicago, IL) prior to the American Transplant Congress in which a multidisciplinary group convened to identify the unmet research needs related to medication NA in transplantation. Thought leaders in the field presented the past, present, and future directions of medication NA with the primary outcome of designing, developing, and ranking targeted interventions into a dynamic research agenda to identify which interventions maintained effects over time. Break-out sessions were created based on the five World Health Organization (WHO) dimensions of adherence. Participants were then organized into the newly formed AST Transplant Pharmacy Adherence Consortium (AST TPAC) research group. This meeting report summarizes the content of the symposium, and the development, background, and future directions of the AST TPAC.

Absence of the Effect of Pretransplant Body Mass Index on Post Kidney Transplant Outcomes.

CONTEXT: Obesity has been reported as risk factor for reduced posttransplant graft and patient survival and increased delayed graft function (DGF). OBJECTIVE: The purpose of this work is to analyze the effect of body mass index (BMI) on defined transplant outcomes in patients transplanted under defined guidelines in a kidney transplant program. DESIGN: Review of a prospectively collected database in renal transplant recipients receiving rabbit antithymocyte globulin induction, mycophenolate mofetil, tacrolimus, and early corticosteroid withdrawal between 2001 and 2011. SETTING: This review was conducted in a single abdominal transplant program in the United States. MAIN OUTCOME MEASURES: Primary outcome was death-censored graft survival categorized by posttransplant body mass groups. Secondary outcomes included DGF as well as patient survival. RESULTS: Four hundred sixty seven patients were identified. No difference was observed in graft survival or DGF between BMI groups. One-year, death-censored graft survival and patient survival rates ranged from 97.5% to 100% and 96.6% to 100%, respectively. Delayed graft function was uncommon across all BMI groups, ranging from 5.3% to 9.1%, with the lowest incidence in patients with a BMI ≥ 35 kg/m(2). Biopsy-proven acute rejection rates at 1 year were similar across all groups (10.1%-14%) as were estimated glomerular filtration rates were at 1, 3, and 5 years. CONCLUSION: Our results do not show an effect of BMI on posttransplant outcomes, suggesting that relaxation of BMI criteria may be warranted for recipient selection.

Impact of recipient morbid obesity on outcomes after liver transplantation.

The aim of this study was to analyze the impact of morbid obesity in recipients on peritransplant resource utilization and survival outcomes. Using a linkage between the University HealthSystem Consortium and Scientific Registry of Transplant Recipients databases, we identified 12 445 patients who underwent liver transplantation (LT) between 2007 and 2011 and divided them into two cohorts based on recipient body mass index (BMI; <40 vs. ≥40 kg/m²). Recipients with BMI ≥40 comprised 3.3% (n = 416) of all LTs in the studied population. There were no significant differences in donor characteristics between two groups. Recipients with BMI ≥40 were significant for being female, diabetic, and with NASH cirrhosis. Patients with a BMI ≥40 had a higher median MELD score, limited physical capacity, and were more likely to be hospitalized at LT. BMI ≥40 recipients had higher post-LT length of stay and were less often discharged to home. With a median follow-up of 2 years, patient and graft survival were equivalent between the two groups. In conclusion, morbidly obese LT recipients appear sicker at time of LT with an increase in resource utilization but have similar short-term outcomes.

Lack of Clostridium difficile infection in patients treated with rifaximin for hepatic encephalopathy: a retrospective analysis.

GOALS: The purpose of this study was to assess the incidence of Clostridium difficile infection in patients who received rifaximin for the treatment of hepatic encephalopathy (HE). METHODS: Medical charts of patients who received rifaximin for the treatment of HE were reviewed. The number of patients who developed diarrhea during treatment with rifaximin and results of latex agglutination assays to detect C. difficile in stool samples were analyzed. RESULTS: A total of 211 patients received rifaximin for HE. Of these, 152 were treated in a university practice and 59 were treated in community practices. The mean dose of rifaximin was 1055 mg/d (range, 600 to 1600 mg/d) for a mean duration of 250 days (range, 180 to 385 d). Eighteen patients developed diarrhea during rifaximin treatment. None of these patients tested positive for C. difficile. CONCLUSIONS: This study demonstrates that treatment of HE with the safe, nonsystemic, gut-selective antibiotic rifaximin was not associated with the development of C. difficile infection.

Durability of rifaximin response in hepatic encephalopathy.

GOALS: To evaluate the durability of the response to rifaximin for treatment of hepatic encephalopathy (HE). BACKGROUND: The nonsystemic antibiotic rifaximin has been approved for maintenance of HE remission, and several studies have indicated the efficacy of rifaximin for acute HE; however, the duration of therapeutic response for >6 months remains unknown. STUDY: Medical records of patients with cirrhosis who received rifaximin maintenance therapy for HE between January 2004 and May 2009 were reviewed. Model for end-stage liver disease (MELD) scores were obtained every 3 months during therapy. RESULTS: Of 203 patients with HE (Conn score ≥2), 149 received rifaximin monotherapy (400 to 1600 mg/d) and 54 received rifaximin (600 to 1200 mg/d) and lactulose (90 mL/d) dual therapy. Maintenance of HE remission for 1 year occurred in 81% and 67% of patients who received rifaximin monotherapy and rifaximin and lactulose dual therapy, respectively. Patient populations with a baseline mean MELD score ≤20 had few overt HE events, suggesting increased response to rifaximin in these patients. CONCLUSIONS: Rifaximin is effective for the management of HE in patients with cirrhosis, particularly in populations with MELD scores ≤20. Additional studies are needed to investigate the potential association between MELD scores and the efficacy of HE treatments.

A systematic review of direct acting antiviral therapies in hepatitis C virus-negative liver transplant recipients of hepatitis C-viremic donors.

The introduction of safe and highly effective direct acting antivirals (DAAs) has significantly improved hepatitis C virus (HCV) treatment outcomes after transplant. The solid organ transplant community has sought to identify strategies aimed at increasing the donor pool including the utilization of HCV-viremic organs in HCV-negative recipients. We will review the existing literature to evaluate DAA use for the treatment of HCV viremia post-liver transplant in patients who receive HCV-viremic allografts. A PubMed search was conducted and references for each study were also reviewed to identify additional articles. Randomized controlled trials, cohort studies, case series, and case reports were included if: published in English language, evaluated DAA treatment outcomes after liver only or simultaneous liver-kidney transplantation with HCV-viremic allografts in HCV-negative recipients, and had full-text article availability. Our review included 16 studies and 2 case reports. The majority of liver transplant recipients were treated with a pangenotypic DAA for 12 weeks with a heterogeneous median time to initiation (range 1.7-118 days). Sustained virologic response was assessed in 253 liver transplant patients with 99.6% achieving cure with minimal DAA-attributed adverse drug events. There were 23 reported episodes of rejection, 12 deaths, and 1 graft loss among all studies. Treatment with DAA after transplantation of HCV-viremic livers into HCV-negative recipients appears to be safe and effective; however, long-term outcomes remain unknown. Transplant pharmacists play a key role in the development of center-specific protocols to optimize post-transplant outcomes in this unique patient population.

The cost-effectiveness of screening for chronic hepatitis B infection in the United States.

BACKGROUND: Hepatitis B virus (HBV) continues to cause significant morbidity and mortality in the United States. Current guidelines suggest screening populations with a prevalence of ≥2%. Our objective was to determine whether this screening threshold is cost-effective and whether screening lower-prevalence populations might also be cost-effective. METHODS: We developed a Markov state transition model to examine screening of asymptomatic outpatients in the United States. The base case was a 35-year-old man living in a region with an HBV infection prevalence of 2%. Interventions (versus no screening) included screening for Hepatitis B surface antigen followed by treatment of appropriate patients with (1) pegylated interferon-α2a for 48 weeks, (2) a low-cost nucleoside or nucleotide agent with a high rate of developing viral resistance for 48 weeks, (3) prolonged treatment with low-cost, high-resistance nucleoside or nucleotide, or (4) prolonged treatment with a high-cost nucleoside or nucleotide with a low rate of developing viral resistance. Effectiveness was measured in quality-adjusted life years (QALYs) and costs in 2008 US dollars. RESULTS: Screening followed by treatment with a low-cost, high-resistance nucleoside or nucleotide was cost-effective ($29,230 per QALY). Sensitivity analyses revealed that screening costs <$50,000 per QALY in extremely low-risk populations unless the prevalence of chronic HBV infection is <.3%. CONCLUSIONS: The 2% threshold for prevalence of chronic HBV infection in current Centers for Disease Control and Prevention/US Public Health Service screening guidelines is cost-effective. Furthermore, screening of adults in the United States in lower-prevalence populations (eg, as low as .3%) also is likely to be cost-effective, suggesting that current health policy should be reconsidered.

Implications for body weight extremes in solid organ transplantation.

The pharmacokinetic profiles of medications are altered in overweight and underweight patients, but few studies have described these differences in patients with body mass index extremes. As solid organ transplant programs expand their candidate selection criteria to accommodate a growing population of patients with weight extremes, it has become imperative to understand and evaluate the impact weight extremes have on the pharmacokinetics of life-sustaining immunosuppression in this population. This review will describe pharmacokinetic and dosing considerations for weight extremes in solid organ transplant recipients, including changes following bariatric surgeries, non-pharmacologic and pharmacologic management strategies for weight loss and gain, and potential drug-drug interactions with popular weight management products.

Rifaximin for the treatment of recurrent Clostridium difficile infection after liver transplantation: A case series.

Previous data have suggested that the nonsystemic antibiotic rifaximin may be effective for the treatment of Clostridium difficile infection (CDI). This single-center retrospective study evaluated the efficacy of rifaximin for the treatment of CDI refractory to standard treatments in patients who had received liver transplants. Among 205 patients who had received liver transplants between July 2001 and December 2007, 3 patients with a confirmed diagnosis of C. difficile experienced recurrent diarrhea even though they received standard therapy. Patient 1, a 56-year-old male, patient 2, a 62-year-old male, and patient 3, a 73-year-old female, developed CDIs 190, 318, and 2310 days after transplantation, respectively. All patients experienced symptom recurrences after oral metronidazole therapy (250 mg 3 times daily for either 14 or 28 days) and after oral vancomycin therapy (125 mg 4 times daily for 14 days). Long-term vancomycin treatment (ie, 28 days) was required for patients 1 and 2. Vancomycin was discontinued in patient 3 because of increased creatinine levels. Oral rifaximin (400 mg 3 times daily) was initiated immediately after discontinuation of vancomycin therapy. Within 36 to 48 hours of the initiation of rifaximin treatment, diarrheal symptoms were resolved in all patients. After completing a 28-day course of rifaximin, patient 1 remained symptom-free during 185 days of follow-up, and patient 2 remained symptom-free during 250 days of follow-up. Patient 3 reported no symptoms within 155 days after the completion of rifaximin treatment. These findings suggest that rifaximin may be effective for the treatment of recurrent CDI and may provide a therapeutic option for CDI in immunocompromised patients.