Kidney transplant outcomes in children and adolescents with systemic lupus erythematosus.

BACKGROUND: Literature supports equivalent kidney transplant outcomes in adults with systemic lupus erythematosus (SLE) compared with those without SLE. However, there are conflicting and scant data on kidney transplant outcomes, as well as controversy over optimal timing of transplantation, in children and adolescents with SLE. METHODS: Analysis included kidney-only transplant recipients aged 2-21 years from 2000 to 2017 enrolled in the Organ Procurement and Transplant Network (OPTN). The relationship between diagnosis (SLE n = 457, non-SLE glomerular disease n = 4492, and non-SLE non-glomerular disease n = 5605) and transplant outcomes was evaluated. The association between dialysis time and outcomes was analyzed in the SLE group only. RESULTS: In adjusted models, SLE had higher mortality compared with non-SLE glomerular recipients (HR 1.24 CI 1.07-1.44) and non-glomerular recipients (HR 1.42 CI 1.20-1.70). SLE was associated with higher graft failure compared with non-SLE glomerular (HR 1.42 CI 1.20-1.69) and non-glomerular disease (HR 1.67 CI 1.22-2.28). SLE had a higher risk of acute rejection at 1 year compared with non-glomerular disease (HR 1.39 CI 1.03-1.88). There was a decreased risk of delayed graft function compared with non-SLE glomerular disease (HR 0.54, CI 0.36-0.82). There were no significant associations between dialysis time and transplant outcomes in the SLE group. CONCLUSION: SLE in children and adolescents is associated with worse patient and graft survival compared with non-SLE diagnoses. Outcomes in children and adolescents with SLE are not associated with dialysis time. Further studies are needed to assess implications of potential earlier transplantation and shorter time on dialysis prior to transplantation.

An early experience on the effect of solid organ transplant status on hospitalized COVID-19 patients.

We compared the outcome of COVID-19 in immunosuppressed solid organ transplant (SOT) patients to a transplant naïve population. In total, 10 356 adult hospital admissions for COVID-19 from March 1, 2020 to April 27, 2020 were analyzed. Data were collected on demographics, baseline clinical conditions, medications, immunosuppression, and COVID-19 course. Primary outcome was combined death or mechanical ventilation. We assessed the association between primary outcome and prognostic variables using bivariate and multivariate regression models. We also compared the primary endpoint in SOT patients to an age, gender, and comorbidity-matched control group. Bivariate analysis found transplant status, age, gender, race/ethnicity, body mass index, diabetes, hypertension, cardiovascular disease, COPD, and GFR <60 mL/min/1.73 m2 to be significant predictors of combined death or mechanical ventilation. After multivariate logistic regression analysis, SOT status had a trend toward significance (odds ratio [OR] 1.29; 95% CI 0.99-1.69, p = .06). Compared to an age, gender, and comorbidity-matched control group, SOT patients had a higher combined risk of death or mechanical ventilation (OR 1.34; 95% CI 1.03-1.74, p = .027).

Hepatitis C-positive donor to negative recipient kidney transplantation: A real-world experience.

BACKGROUND: Several studies have shown that transplanting a hepatitis C virus (HCV)-negative recipients with a HCV-positive donor is feasible in a research setting. In February 2018, we began transplanting HCV-negative recipients with HCV-positive donors as standard of care. METHODS: All patients, except those with previously cured HCV and those with cirrhosis, were consented for HCV NAT-positive donor kidneys. After transplantation, patients were tested for HCV RNA until viremic. A direct-acting antiviral (DAA) agent was prescribed based on genotype and insurance approval. Sustained virologic response (SVR) at weeks 4 and 12 was recorded. Renal function and death censored graft survival at 1 year were evaluated and compared to recipients of HCV NAT-negative kidneys. RESULTS: A total of 25 HCV NAT-positive donor kidney transplants from February to October 2018 were performed. All patients received basiliximab and maintained with tacrolimus, mycophenolate mofetil, and prednisone. Median time from viremia to start of DAA was 13 (8-22) days. The most common genotype was 1a (60%), followed by 3a (28%). The most commonly prescribed DAA was ledipasvir/sofosbuvir (56%), followed by velpatasvir/sofosbuvir (32%), and then glecaprevir/pibrentasvir (12%). All patients achieved initial SVR12, except one. One patient had a mixed-genotype infection requiring retreatment to achieve SVR12. Death censored graft survival was 96%. Recipients of HCV NAT-positive organs compared to HCV NAT-negative organs received younger donors (mean 35 ± 8.9 vs 45.1 ± 15.7 years; P < .01) and spent less time on the waitlist (median 479 (93-582) vs 1808 (567-2263) days; P = .02). CONCLUSION: HCV NAT-negative recipients can be safely and successfully transplanted with HCV NAT-positive donor kidneys outside of a research protocol. Access to DAA and timely administration of therapy is important and an insurance approval process within the transplant center can be beneficial to patients. A case of mixed-genotype infection was presented, and although not as common, can be successfully treated. HCV organs can expand the organ pool and should no longer be considered experimental. The use of these organs in HCV-negative recipient's decreases waiting time, have excellent outcomes, and should be considered standard of care.

COVID-19 infection in a pediatric kidney transplant population: A single-center experience.

BACKGROUND: The clinical course of SARS-CoV-2 in the pediatric kidney transplant population is not well described. METHODS: We performed a retrospective cohort study of a pediatric kidney transplant population at a New York transplant center. Baseline characteristics and clinical course of patients with SARS-CoV-2 positivity (Ab or PCR) were described, and comparison between COVID-positive and COVID-negative transplant patients was performed. RESULTS: Twenty-two patients had COVID-19 IgG testing performed, eight of whom also had PCR testing. 23% of our cohort had evidence of COVID-19 infection. Four patients had positive IgG only, and one patient had a positive PCR. All five patients with a positive COVID test were female. Two patients had COVID-19 symptoms, which were mild. Of the symptomatic patients, one had a positive PCR at time of symptoms, while the other had a negative PCR during symptoms but subsequently had positive IgG. As compared to patients with COVID-19 negative results, those with COVID-19 positivity were significantly more likely to have a known COVID-19 exposure, and were also more likely to be female. There was no significant difference in time from transplant between the groups. Those in the COVID-positive group had higher baseline antimetabolite dose and CNI troughs, although these did not reach statistical significance. CONCLUSIONS: Pediatric kidney transplant recipients are at risk for development of COVID-19 infection. While this population may be more at risk for SARS-CoV-2 infection due to their immunosuppressed status, their clinical course appears mild and similar to a healthy pediatric population.

COVID-19 in kidney transplant recipients.

There is minimal information on coronavirus disease 2019 (COVID-19) in immunocompromised individuals. We have studied 10 patients treated at 12 adult care hospitals. Ten kidney transplant recipients tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by polymerase chain reaction, and 9 were admitted. The median age was 57 (interquartile range [IQR] 47-67), 60% were male, 40% Caucasian, and 30% Black/African American. Median time from transplant to COVID-19 testing was 2822 days (IQR 1272-4592). The most common symptom was fever, followed by cough, myalgia, chills, and fatigue. The most common chest X-ray and computed tomography abnormality was multifocal patchy opacities. Three patients had no abnormal findings. Leukopenia was seen in 20% of patients, and allograft function was stable in 50% of patients. Nine patients were on tacrolimus and a mycophenolic antimetabolite, and 70% were on prednisone. Hospitalized patients had their antimetabolite agent stopped. All hospitalized patients received hydroxychloroquine and azithromycin. Three patients died (30%), and 5 (50%) developed acute kidney injury. Kidney transplant recipients infected with COVID-19 should be monitored closely in the setting of lowered immunosuppression. Most individuals required hospitalization and presenting symptoms were similar to those of nontransplant individuals.

Posttransplant Outcome of Lean Compared With Obese Nonalcoholic Steatohepatitis in the United States: The Obesity Paradox.

Morbid obesity is considered a relative contraindication for liver transplantation (LT). We investigated if body mass index (BMI; lean versus obese) is a risk factor for post-LT graft and overall survival in nonalcoholic steatohepatitis (NASH) and non-NASH patients. Using the United Network for Organ Sharing (UNOS) database, LT recipients from January 2002 to June 2013 (age ≥18 years) with follow-up until 2017 were included. The association of BMI categories calculated at LT with graft and overall survival after LT were examined. After adjusting for confounders, all obesity cohorts (overweight and class 1, class 2, and class 3 obesity) among LT recipients for NASH had significantly reduced risk of graft and patient loss at 10 years of follow-up compared with the lean BMI cohort. In contrast, the non-NASH group of LT recipients had no increased risk for graft and patient loss for overweight, class 1, and class 2 obesity groups but had significantly increased risk for graft (P < 0.001) and patient loss (P = 0.005) in the class 3 obesity group. In this retrospective analysis of the UNOS database, adult recipients selected for first LT and NASH patients with the lowest BMI have the worse longterm graft and patient survival as opposed to non-NASH patients where the survival was worse with higher BMI.

Longterm Impact of Living Liver Donation: A Self-Report of the Donation Experience.

Outcomes for adult-to-adult living liver donors (LDs) are largely based on short-term data drawn from single-center studies. The aim of this study was to determine how living liver donation (LLD) impacts self-reported quality-of-life (QOL) up to 6 years after donation in a sample of residents from New York State. New York transplant programs are state-mandated to track LDs as part of a quality assurance and patient safety effort. Donor-reported QOL within 1 year of donation and longitudinal data over a 10-year period were analyzed. Self-reported surveys include the following domains: employment, finances, health/life insurance, activities of daily living, physical/emotional health, donor experience, relationships, and LD opinions. There were 220 LDs in New York (2004-2013) who completed a survey over the 10-year period with many donors completing surveys at several points in time. Overall, longterm LDs remain as comfortable about LLD as they were during the first year after donation (95%). The majority of LDs reported feeling as well as before LLD (72%). At 1 year after donation, 60% of subjects self-reported medical problems, and 30% reported emotional issues. However, the majority reported that they would willingly donate again. In conclusion, LDs remain satisfied with their decision to donate over time. A minority of LDs report longterm medical and emotional issues. The conclusions provide information for educational interventions to improve informed choice to those considering donation.

An unusual case of Kaposi sarcoma masquerading as cystitis in a kidney transplant recipient.

Human Herpes Virus-8 (HHV-8) may reactivate in immunocompromised patients including recipients of solid organ transplants. Reactivation of HHV-8 may result in Kaposi sarcoma (KS). KS typically occurs with dermatologic involvement but can affect virtually any other organ; most commonly the gastrointestinal tract. We present a diagnostically challenging case of KS in a South American woman 7 months after kidney transplant. She presented with recurrent urinary tract infection manifested by pelvic pain and dysuria. Imaging studies revealed bladder thickening with pelvic lymphadenopathy. Findings on tissue biopsied from the bladder and lymph nodes were consistent with KS. Her skin was not affected. This case illustrates that KS and other HHV-8-related diseases should be on the differential diagnosis as a cause of mass lesions as well as lymphadenopathy in transplant recipients. The case exemplifies the need to pursue a tissue diagnosis in immunocompromised patients when a diagnosis is uncertain.

Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis.

BACKGROUND: As the population that is infected with the hepatitis C virus (HCV) ages, the number of patients with decompensated cirrhosis is expected to increase. METHODS: We conducted a phase 3, open-label study involving both previously treated and previously untreated patients infected with HCV genotypes 1 through 6 who had decompensated cirrhosis (classified as Child-Pugh-Turcotte class B). Patients were randomly assigned in a 1:1:1 ratio to receive the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir once daily for 12 weeks, sofosbuvir-velpatasvir plus ribavirin for 12 weeks, or sofosbuvir-velpatasvir for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: Of the 267 patients who received treatment, 78% had HCV genotype 1, 4% genotype 2, 15% genotype 3, 3% genotype 4, and less than 1% genotype 6; no patients had genotype 5. Overall rates of sustained virologic response were 83% (95% confidence interval [CI], 74 to 90) among patients who received 12 weeks of sofosbuvir-velpatasvir, 94% (95% CI, 87 to 98) among those who received 12 weeks of sofosbuvir-velpatasvir plus ribavirin, and 86% (95% CI, 77 to 92) among those who received 24 weeks of sofosbuvir-velpatasvir. Post hoc analysis did not detect any significant differences in rates of sustained virologic response among the three study groups. Serious adverse events occurred in 19% of patients who received 12 weeks of sofosbuvir-velpatasvir, 16% of those who received 12 weeks of sofosbuvir-velpatasvir plus ribavirin, and 18% of those who received 24 weeks of sofosbuvir-velpatasvir. The most common adverse events were fatigue (29%), nausea (23%), and headache (22%) in all patients and anemia (31%) in the patients receiving ribavirin. CONCLUSIONS: Treatment with sofosbuvir-velpatasvir with or without ribavirin for 12 weeks and with sofosbuvir-velpatasvir for 24 weeks resulted in high rates of sustained virologic response in patients with HCV infection and decompensated cirrhosis. (Funded by Gilead Sciences; ASTRAL-4 ClinicalTrials.gov number, NCT02201901.).

Extracorporeal cellular therapy (ELAD) in severe alcoholic hepatitis: A multinational, prospective, controlled, randomized trial.

Severe alcoholic hepatitis (sAH) is associated with a poor prognosis. There is no proven effective treatment for sAH, which is why early transplantation has been increasingly discussed. Hepatoblastoma-derived C3A cells express anti-inflammatory proteins and growth factors and were tested in an extracorporeal cellular therapy (ELAD) study to establish their effect on survival for subjects with sAH. Adults with sAH, bilirubin ≥8 mg/dL, Maddrey's discriminant function ≥ 32, and Model for End-Stage Liver Disease (MELD) score ≤ 35 were randomized to receive standard of care (SOC) only or 3-5 days of continuous ELAD treatment plus SOC. After a minimum follow-up of 91 days, overall survival (OS) was assessed by using a Kaplan-Meier survival analysis. A total of 203 subjects were enrolled (96 ELAD and 107 SOC) at 40 sites worldwide. Comparison of baseline characteristics showed no significant differences between groups and within subgroups. There was no significant difference in serious adverse events between the 2 groups. In an analysis of the intent-to-treat population, there was no difference in OS (51.0% versus 49.5%). The study failed its primary and secondary end point in a population with sAH and with a MELD ranging from 18 to 35 and no upper age limit. In the prespecified analysis of subjects with MELD < 28 (n = 120), ELAD was associated with a trend toward higher OS at 91 days (68.6% versus 53.6%; P = .08). Regression analysis identified high creatinine and international normalized ratio, but not bilirubin, as the MELD components predicting negative outcomes with ELAD. A new trial investigating a potential benefit of ELAD in younger subjects with sufficient renal function and less severe coagulopathy has been initiated. Liver Transplantation 24 380-393 2018 AASLD.

Outcomes of underweight, overweight, and obese pediatric kidney transplant recipients.

BACKGROUND: Obesity is a risk factor for poor transplant outcomes in the adult population. The effect of pre-transplant weight on pediatric kidney transplantation is conflicting in the existing literature. METHODS: Data was collected from the Organ Procurement and Transplantation Network (OPTN) database on recipients aged 2-21 years who received a kidney-only transplant from 1987 to 2017. Recipients were categorized into underweight, normal, overweight, and obese cohorts. Using adjusted regression models, the relationship between recipient weight and various graft outcomes (delayed graft function [DGF], acute rejection, prolonged hospitalization, graft failure, mortality) was examined. RESULTS: 18,261 transplant recipients (mean age 14.1 ± 5.5 years) were included, of which 8.7% were underweight, 14.8% were overweight, and 15% were obese. Obesity was associated with greater odds of DGF (OR 1.3 95% CI 1.13-1.49, p < 0.001), acute rejection (OR 1.23 95% CI 1.06-1.43, p < 0.01), and prolonged hospitalization (OR 1.35 95% CI 1.17-1.54, p < 0.001) as well as greater hazard of graft failure (HR 1.13 95% CI 1.05-1.22, p = 0.001) and mortality (HR 1.19 95% CI 1.05-1.35, p < 0.01). The overweight cohort had an increased risk of graft failure (HR 1.08 95% CI 1.001-1.16, p = 0.048) and increased odds of DGF (OR 1.2 95% CI 1.04-1.38, p = 0.01) and acute rejection (OR 1.18 95% CI 1.01-1.38, p = 0.04). When stratified by age group, the increased risk was realized among younger and older age groups for obese and overweight. Underweight had lower risk of 1-year graft failure (HR 0.82 95% CI 0.71-0.94, p < 0.01), overall graft failure in the 13-17-yr. age group (HR 0.84 95% CI 0.72-0.99, p = 0.03) and acute rejection in the 2-5-yr. age group (OR 0.24 95% CI 0.09-0.66, p < 0.01). CONCLUSION: Pre-transplant weight status and age impact pediatric kidney transplant outcomes. Recipient underweight status seems to be protective against adverse outcomes while overweight and obesity may lead to poorer graft and patient outcomes.

Serum Tumor Markers Provide Refined Prognostication in Selecting Liver Transplantation Candidate for Hepatocellular Carcinoma Patients Beyond the Milan Criteria.

OBJECTIVE: To develop and validate a model to predict tumor recurrence after living donor liver transplantation (LDLT) (MoRAL) for hepatocellular carcinoma (HCC) beyond the Milan criteria (MC). BACKGROUND: Some subgroups of HCC exceeding the MC experience substantial benefit from LDLT. METHODS: This multicenter study included a total of 566 consecutive patients who underwent LDLT in Korea: the beyond-MC cohort (n = 205, the derivation [n = 92] and validation [n = 113] sets) and the within-MC cohort (n = 361). The primary endpoint was time-to-recurrence. RESULTS: Using multivariate Cox proportional hazard model, we derived the MoRAL score using serum levels of protein induced by vitamin K absence-II and alpha-fetoprotein, which provided a good discriminant function on time-to-recurrence (concordance index = 0.88). Concordance index was maintained similarly on both internal and external validations (mean 0.87 and 0.84, respectively). At cut off of 314.8 (75th percentile value), a low MoRAL score (≤314.8) was associated with significantly longer recurrence-free (versus > 314.8, HR = 5.29, P < 0.001) and overall survivals (HR = 2.59, P = 0.001) in the beyond-MC cohort. The 5-year recurrence-free and overall survival rates of beyond-MC patients with a low MoRAL score were as high as 66.3% and 82.6%, respectively. The within-MC patients with a high MoRAL score showed a higher risk of recurrence than beyond-MC patients with a low MoRAL score (HR = 2.56, P = 0.035). The MoRAL score was significantly correlated with explant histology. CONCLUSIONS: This new model using protein induced by vitamin K absence-II and alpha-fetoprotein provides refined prognostication. Among beyond-MC HCC patients, those with a MoRAL score ≤314.8 and without extrahepatic metastasis might be potential candidates for LDLT.

Sofosbuvir and ribavirin for treatment of compensated recurrent hepatitis C virus infection after liver transplantation.

BACKGROUND & AIMS: Interferon alfa-based regimens used to treat recurrent hepatitis C virus (HCV) infection after liver transplantation are poorly tolerated, associated with generally modest efficacy, and can interact with immunosuppressive agents. We evaluated the efficacy and safety of an interferon-free regimen of the nucleotide polymerase inhibitor sofosbuvir combined with ribavirin for 24 weeks in treating post-transplantation HCV infection. METHODS: In a prospective, multicenter, open-label pilot study, we enrolled patients with compensated recurrent HCV infection of any genotype after a primary or secondary liver transplantation. All patients received 24 weeks of sofosbuvir 400 mg daily and ribavirin starting at 400 mg daily, which was adjusted according to creatinine clearance and hemoglobin values. The primary end point was sustained virologic response 12 weeks after treatment. RESULTS: Of the 40 patients enrolled and treated, 78% were male, 85% were white, 83% had HCV genotype 1, 40% had cirrhosis (based on biopsy), and 88% had been previously treated with interferon. Sustained virologic response 12 weeks after treatment was achieved by 28 of 40 patients (70%; 90% confidence interval: 56%-82%). Relapse accounted for all cases of virologic failure. No patients had detectable viral resistance during or after treatment. The most common adverse events were fatigue (30%), diarrhea (28%), and headache (25%). In addition, 20% of the subjects experienced anemia. Two patients discontinued study treatment because of adverse events, which were considered unrelated to study treatment. No deaths, graft losses, or episodes of rejection occurred. No interactions with any concomitant immunosuppressive agents were reported. CONCLUSIONS: Sofosbuvir and ribavirin combination therapy for 24 weeks is an effective and well-tolerated interferon-free treatment for post-transplantation HCV infection. EudraCT, Number: 2012-002417-19; ClinicalTrials.gov, Number: NCT01687270.

Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease.

BACKGROUND & AIMS: There are no effective and safe treatments for chronic hepatitis C virus (HCV) infection of patients who have advanced liver disease. METHODS: In this phase 2, open-label study, we assessed treatment with the NS5A inhibitor ledipasvir, the nucleotide polymerase inhibitor sofosbuvir, and ribavirin in patients infected with HCV genotypes 1 or 4. Cohort A enrolled patients with cirrhosis and moderate or severe hepatic impairment who had not undergone liver transplantation. Cohort B enrolled patients who had undergone liver transplantation: those without cirrhosis; those with cirrhosis and mild, moderate, or severe hepatic impairment; and those with fibrosing cholestatic hepatitis. Patients were assigned randomly (1:1) to receive 12 or 24 weeks of a fixed-dose combination tablet containing ledipasvir and sofosbuvir, once daily, plus ribavirin. The primary end point was sustained virologic response at 12 weeks after the end of treatment (SVR12). RESULTS: We enrolled 337 patients, 332 (99%) with HCV genotype 1 infection and 5 (1%) with HCV genotype 4 infection. In cohort A (nontransplant), SVR12 was achieved by 86%-89% of patients. In cohort B (transplant recipients), SVR12 was achieved by 96%-98% of patients without cirrhosis or with compensated cirrhosis, by 85%-88% of patients with moderate hepatic impairment, by 60%-75% of patients with severe hepatic impairment, and by all 6 patients with fibrosing cholestatic hepatitis. Response rates in the 12- and 24-week groups were similar. Thirteen patients (4%) discontinued the ledipasvir and sofosbuvir combination prematurely because of adverse events; 10 patients died, mainly from complications related to hepatic decompensation. CONCLUSION: The combination of ledipasvir, sofosbuvir, and ribavirin for 12 weeks produced high rates of SVR12 in patients with advanced liver disease, including those with decompensated cirrhosis before and after liver transplantation. ClinTrials.gov: NCT01938430.

Lesson From the New York City Out-of-Hospital Uncontrolled Donation After Circulatory Determination of Death Program.

STUDY OBJECTIVE: In 2006, the Institute of Medicine emphasized substantial potential to expand organ donation opportunities through uncontrolled donation after circulatory determination of death (uDCDD). We pilot an out-of-hospital uDCDD kidney program for New York City in partnership with communities that it was intended to benefit. We evaluate protocol process and outcomes while identifying barriers to success and means for improvement. METHODS: We conducted a prospective, participatory action research study in Manhattan from December 2010 to May 2011. Daily from 4 to 12 pm, our organ preservation unit monitored emergency medical services (EMS) frequencies for cardiac arrests occurring in private locations. After EMS providers independently ordered termination of resuscitation, organ preservation unit staff determined clinical eligibility and donor status. Authorized parties, persons authorized to make organ donation decisions, were approached about in vivo preservation. The study population included organ preservation unit staff, authorized parties, passersby, and other New York City agency personnel. Organ preservation unit staff independently documented shift activities with daily operations notes and teleconference summaries that we analyzed with mixed qualitative and quantitative methods. RESULTS: The organ preservation unit entered 9 private locations; all the deceased lacked previous registration, although 4 met clinical screening eligibility. No kidneys were recovered. We collected 837 notes from 35 organ preservation unit staff. Despite frequently recounting protocol breaches, most responses from passersby including New York City agencies were favorable. No authorized parties were offended by preservation requests, yielding a Bayesian posterior median 98% (95% credible interval 76% to 100%). CONCLUSION: In summary, the New York City out-of-hospital uDCDD program was not feasible. There were frequent protocol breaches and confusion in determining clinical eligibility. In the small sample of authorized persons we encountered during the immediate grieving period, negative reactions were infrequent.

Conversion from twice daily tacrolimus capsules to once daily extended-release tacrolimus (LCP-Tacro): phase 2 trial of stable liver transplant recipients.

LCP-Tacro is an extended-release formulation of tacrolimus designed for once-daily dosing. Studies in renal transplantation demonstrate greater bioavailability with similar safety and efficacy vs. twice-daily tacrolimus capsules. In this phase 2 study, adult stable liver transplant patients on tacrolimus capsules (Prograf) twice-daily were converted to tacrolimus tablets (LCP-Tacro) once-daily; patients continued on LCP-Tacro once-daily for days 8-21; target trough levels were 5-15 ng/mL; 24-hour pharmacokinetic (PK) assessments were done on days 7 (baseline pre-switch), 14, and 21. A 6 month extension study phase evaluated PK and safety following a total of 52 weeks of LCP-Tacro. Fifty-seven patients completed LCP-Tacro dosing in the core study; 43 completed the extension phase. The mean conversion ratio was 0.71 (Prograf:LCP-Tacro). PK data demonstrated consistent exposure (AUC) at the lower conversion dose. Cmax , Cmax /Cmin ratio, percent fluctuation and swing were significantly (P<0.001) lower and Tmax significantly (P<0.001) longer for LCP-Tacro vs. Prograf. AUC24 and Cmin correlation coefficients after 7 and 14 days of therapy were ≥0.93. There were no significant differences in PK parameters at week 26 vs. 14. One patient experienced an unrelated serious adverse event (SAE) during the core study and discontinued. There were six unrelated SAEs in the extension and 1 possibly related (rejection) that resolved; there were 3 discontinuations due to AEs during the extension. In this study, patients were safely converted from Prograf twice-daily to LCP-Tacro. The greater bioavailability of LCP-Tacro allowed for once-daily dosing and similar (AUC) exposure at a dose approximately 30% less than the total daily dose of Prograf. LCP-Tacro displayed significantly lower peak and peak-trough fluctuations. LCP-Tacro administered over one year was well tolerated with no new safety concerns.

Fidaxomicin versus conventional antimicrobial therapy in 59 recipients of solid organ and hematopoietic stem cell transplantation with Clostridium difficile-associated diarrhea.

The feasibility of fidaxomicin versus vancomycin and metronidazole (conventional therapy) was assessed in 59 transplant recipients with 61 episodes of Clostridium difficile-associated diarrhea (CDAD). Overall clinical cure was achieved in 86% of episodes, and in 7% of episodes, infection recurred. Fidaxomicin was well tolerated. Clinical cures were not significantly different compared with conventional therapy (67% versus 89%, respectively; P = 0.06). Univariate analysis of predictors for lack of clinical cure included continued use of broad-spectrum systemic antibiotics (P = 0.026) and prior diagnosis of CDAD (95% confidence interval, 1.113 to 19.569; odds ratio, 4.667; P = 0.041). New-onset vancomycin-resistant Enterococcus (VRE) colonization was not noted after fidaxomicin therapy alone. However, this occurred in 10 of 28 patients (36%) following conventional therapy, and 2 of 3 patients with subsequent bacteremia died.

Rifaximin treatment in hepatic encephalopathy.

BACKGROUND: Hepatic encephalopathy is a chronically debilitating complication of hepatic cirrhosis. The efficacy of rifaximin, a minimally absorbed antibiotic, is well documented in the treatment of acute hepatic encephalopathy, but its efficacy for prevention of the disease has not been established. METHODS: In this randomized, double-blind, placebo-controlled trial, we randomly assigned 299 patients who were in remission from recurrent hepatic encephalopathy resulting from chronic liver disease to receive either rifaximin, at a dose of 550 mg twice daily (140 patients), or placebo (159 patients) for 6 months. The primary efficacy end point was the time to the first breakthrough episode of hepatic encephalopathy. The key secondary end point was the time to the first hospitalization involving hepatic encephalopathy. RESULTS: Rifaximin significantly reduced the risk of an episode of hepatic encephalopathy, as compared with placebo, over a 6-month period (hazard ratio with rifaximin, 0.42; 95% confidence interval [CI], 0.28 to 0.64; P<0.001). A breakthrough episode of hepatic encephalopathy occurred in 22.1% of patients in the rifaximin group, as compared with 45.9% of patients in the placebo group. A total of 13.6% of the patients in the rifaximin group had a hospitalization involving hepatic encephalopathy, as compared with 22.6% of patients in the placebo group, for a hazard ratio of 0.50 (95% CI, 0.29 to 0.87; P=0.01). More than 90% of patients received concomitant lactulose therapy. The incidence of adverse events reported during the study was similar in the two groups, as was the incidence of serious adverse events. CONCLUSIONS: Over a 6-month period, treatment with rifaximin maintained remission from hepatic encephalopathy more effectively than did placebo. Rifaximin treatment also significantly reduced the risk of hospitalization involving hepatic encephalopathy. (ClinicalTrials.gov number, NCT00298038.)

Randomized trial of emtricitabine/tenofovir disoproxil fumarate after hepatitis B immunoglobulin withdrawal after liver transplantation.

Long-term prophylaxis with hepatitis B immunoglobulin (HBIG) for the prevention of hepatitis B virus (HBV) recurrence after orthotopic liver transplantation (OLT) in patients with chronic HBV infection is inconvenient and costly. This randomized, prospective phase 2 study compared emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) after HBIG withdrawal to FTC/TDF plus HBIG for the prevention of HBV recurrence after OLT. Forty patients with a median time since liver transplantation of 3.4 years (interquartile range = 1.9-5.6 years) received 24 weeks of open-label FTC/TDF plus HBIG before randomization. Patients who maintained confirmed viral suppression were randomized to continue FTC/TDF plus HBIG (n = 19) or receive FTC/TDF alone (n = 18) for an additional 72 weeks. No patient experienced HBV recurrence through 72 weeks of the study while he or she was receiving the randomized treatment. Both treatment arms were safe and well tolerated; no serious or severe drug-related adverse events were observed. Renal function was consistent with that observed in a posttransplant population. The withdrawal of HBIG after 6 months' treatment with FTC/TDF should be considered in liver transplant recipients to prevent chronic HBV recurrence.