Liver Transplantation Using Hepatitis C Virus-Viremic Donors Into Hepatitis C Virus-Aviremic Recipients as Standard of Care.

Liver transplantation (LT) using allografts from hepatitis C virus (HCV)-viremic/nucleic acid testing-positive donors' (DNAT+) organs into HCV-aviremic recipients (rHCV-) has been limited owing to nearly universal HCV transmission and concerns regarding availability, safety, and efficacy post-LT with direct-acting antiviral (DAA) therapy. We report our experience of LT using DNAT+ organs into rHCV- as a routine standard of care. Following verification of DAA access, absence of critical drug-drug interactions (DDIs) with DAAs, and informed consent, allocated DNAT+ organs were offered to patients on the waiting list for LT irrespective of recipient HCV status. Between June 2018 and December 2019, 292/339 rHCV- received an LT. Forty-seven patients were excluded from analysis because of recipient HCV viremia, refusal to receive DNAT+ organs, or inability to receive DAA therapy post-LT. Of these 292 patients, 61 rHCV- received DNAT+ livers (study group), and 231 rHCV- received DNAT- (aviremic donors [nuclear acid test-negative donors]) livers (control group). Recipient and donor characteristics as well as 1-year post-LT patient and graft survival were similar between groups. In the study group, 4 patients died, and 1 patient required retransplantation within the first year post-LT (all unrelated to HCV); 56 patients received DAA therapy, with a median time from LT to the start of DAA treatment of 66.9 days (interquartile range [IQR], 36-68.5), and 51 patients completed DAA treatment, all achieving sustained virologic response for 12 or more weeks (SVR-12) (1 patient required retreatment owing to relapse following initial DAA therapy). No patients had evidence of fibrosing cholestatic hepatitis or extrahepatic manifestations of HCV. This report indicates that transplantation of DNAT+ livers into rHCV- and subsequent DAA therapy is associated with clinical outcomes comparable to those achieved with DNAT- allografts.

Daclatasvir combined with sofosbuvir or simeprevir in liver transplant recipients with severe recurrent hepatitis C infection.

Daclatasvir (DCV) is a potent, pangenotypic nonstructural protein 5A inhibitor with demonstrated antiviral efficacy when combined with sofosbuvir (SOF) or simeprevir (SMV) with or without ribavirin (RBV) in patients with chronic hepatitis C virus (HCV) infection. Herein, we report efficacy and safety data for DCV-based all-oral antiviral therapy in liver transplantation (LT) recipients with severe recurrent HCV. DCV at 60 mg/day was administered for up to 24 weeks as part of a compassionate use protocol. The study included 97 LT recipients with a mean age of 59.3 ± 8.2 years; 93% had genotype 1 HCV and 31% had biopsy-proven cirrhosis between the time of LT and the initiation of DCV. The mean Model for End-Stage Liver Disease (MELD) score was 13.0 ± 6.0, and the proportion with Child-Turcotte-Pugh (CTP) A/B/C was 51%/31%/12%, respectively. Mean HCV RNA at DCV initiation was 14.3 × 6 log10 IU/mL, and 37% had severe cholestatic HCV infection. Antiviral regimens were selected by the local investigator and included DCV+SOF (n = 77), DCV+SMV (n = 18), and DCV+SMV+SOF (n = 2); 35% overall received RBV. At the end of treatment (EOT) and 12 weeks after EOT, 88 (91%) and 84 (87%) patients, respectively, were HCV RNA negative or had levels <43 IU/mL. CTP and MELD scores significantly improved between DCV-based treatment initiation and last contact. Three virological breakthroughs and 2 relapses occurred in patients treated with DCV+SMV with or without RBV. None of the 8 patient deaths (6 during and 2 after therapy) were attributed to therapy. In conclusion, DCV-based all-oral antiviral therapy was well tolerated and resulted in a high sustained virological response in LT recipients with severe recurrent HCV infection. Most treated patients experienced stabilization or improvement in their clinical status.

Phase II study of avatrombopag in thrombocytopenic patients with cirrhosis undergoing an elective procedure.

BACKGROUND & AIMS: This is a phase II multicentre study to investigate the efficacy and safety of avatrombopag (E5501), an investigational second-generation thrombopoietin receptor agonist, administered one week prior to elective procedures in patients with thrombocytopenia secondary to cirrhosis. METHODS: Adults with cirrhosis and platelet counts ⩾10 to ⩽58×10(9)/L were randomized to placebo or avatrombopag in two sequential cohorts. Cohort A: placebo vs. one of 3 different doses (100mg loading dose followed by 20, 40, or 80 mg/day on days 2-7) of a first-generation avatrombopag formulation. Cohort B: placebo vs. one of 2 different doses (80 mg loading dose followed by 10 mg/day for days 2-7, or 20mg/day for days 2-4) of a second-generation avatrombopag formulation. Primary end point was achievement of a platelet increase of ⩾20×10(9)/L from baseline and >50×10(9)/L at least once during days 4-8. RESULTS: A total of 130 patients were randomized: 93 patients (51, cohort A; 42, cohort B) to avatrombopag and 37 (16, cohort A; 21 cohort B) to placebo. The primary end point was achieved by 49.0% of treated patients in cohort A and 47.6% in cohort B compared to 6.3% and 9.5% of controls; a dose response was seen. Each avatrombopag regimen had a higher proportion of responders compared with their respective cohort placebo arms (p<0.01), except for the 100/40 mg group in cohort A (p=0.17). The most common adverse events were nausea, fatigue, and headache. One patient in the (100/80) avatrombopag group, without a Doppler assessment at screening was diagnosed with portal vein thrombosis during post-treatment follow-up. CONCLUSIONS: In this study avatrombopag was generally well-tolerated and increased platelet counts in patients with cirrhosis undergoing elective invasive procedures.

Retreating chronic hepatitis C with daily interferon alfacon-1/ribavirin after nonresponse to pegylated interferon/ribavirin: DIRECT results.

UNLABELLED: Up to 50% of patients with chronic hepatitis C fail to respond to initial therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV). With unsuccessful viral eradication, these patients remain at risk for developing progression of their liver disease. Retreatment with PEG-IFN/RBV yields sustained virologic response (SVR) rates that are under 10%. A wholly synthetic interferon, interferon alfacon-1 or consensus interferon (CIFN) given with RBV, was evaluated in patients who failed initial PEG-IFN/RBV therapy. The intent-to-treat analysis included 487 patients; 245 received CIFN 9 microg/day and RBV, and 242 received CIFN 15 microg/day and RBV. Within this group of patients, 59.3% had documented advanced fibrosis at baseline liver biopsy (stage F3 or F4). SVR rates were 6.9% (17/245 patients) in the 9 microg group and 10.7% (26/242) in the 15 microg group. In the intent-to-treat analysis, SVR rates were higher among patients with a >2-log(10) decrease in hepatitis C virus RNA during prior PEG-IFN/RBV therapy: 11% (4/38) in the 9 mug group and 23% (7/31) in the 15 microg group. Among patients with lower baseline fibrosis scores (F0-F3), SVR rates were 7.8% (15/192) in the 9 microg group and 13.1% (23/175) in the 15 microg group. In this same group of patients (F0-F3), if a >2-log(10) decrease in hepatitis C virus RNA with previous PEG-IFN/RBV treatment was achieved, SVR rates improved to 10.7% and 31.6% in the 9 microg and 15 microg groups, respectively. CIFN/RBV combination retreatment was safe and well tolerated. CONCLUSION: Retreatment of PEG-IFN and RBV nonresponders with CIFN and RBV is safe and efficacious and can be considered a retreatment strategy for patients failing previous therapy with PEG-IFN/RBV, especially in interferon-sensitive patients with lower baseline fibrosis scores.

Interstitial pneumonitis in the transplant patient: consider sirolimus-associated pulmonary toxicity.

Interstitial pneumonia in a transplant patient can have a varied etiology. Sirolimus (Rapamycin; Rapamune) is a popularly used immunosuppressant in solid organ transplantation that has anecdotally been associated with pulmonary toxicity. Sirolimus-induced pulmonary toxicity consists of a range of syndromes that is characterized by the presence of organizing pneumonia, interstitial pneumonitis, pulmonary alveolar proteinosis, focal fibrosis, or by the presence of alveolar hemorrhage. Diagnosis can be challenging and is usually made by exclusion of other etiologies. In this report we present two cases of sirolimus-associated pulmonary toxicity with a review of the literature.

Clinical Evaluation of the Cricoid Pressure Effect on Bag Mask Ventilation, ProSeal Laryngeal Mask Airway Placement and Ventilation.

OBJECTIVE: Supraglottic airway devices can be life-saving in the 'cannot intubate, cannot oxygenate' situation. The cricoid pressure (CP) is considered critical in the prevention of aspiration. The aim of this self-controlled study was to evaluate the effect of CP on the bag mask ventilation (BMV), and the placement of and the ventilation through, the ProSeal laryngeal mask airway (LMA). METHODS: In 60 adult patients undergoing elective surgery, after induction of anaesthesia, the effect of bimanual CP (≈30N) on BMV, ventilation through the ProSeal LMA, its anatomic position and airway seal pressures were evaluated. CP was released, the ProSeal LMA was reseated (appropriate position), the above assessments were repeated, and the effect of CP on the tidal volume (TV) and peak inspiratory pressure (PIP) was noted. RESULTS: Out of 60 patients, the bag mask ventilation with CP was adequate in 25 (41.7%) patients compared to 59 (98.3%) patients without CP; p<0.001. The ventilation via the ProSeal LMA with CP was excellent, adequate and impossible in 0.0% (0), 49.2% (29) and 50.8% (30) patients, respectively, compared to 93.3% (56), 6.7% (4), 0% (0) patients, respectively, without CP; p<0.001. Releasing CP and advancing the ProSeal LMA to its appropriate position significantly improved the ventilation and anatomic position scores; both p<0.001. Airway seal pressures improved significantly without CP compared to with CP; p<0.001). With the ProSeal LMA in a proper position, the CP application resulted in a significant decrease in the mean expired TV (489.14±91.62 vs. 355.08±104.42 mL) with an increase in PIP (16.72±5.01 vs. 30.71±6.74 cmH2O); both p<0.001. CONCLUSION: The application of bimanual CP (≈30N) interferes with the bag mask ventilation and prevents both the correct placement and ventilation via the ProSeal LMA in adult patients.

Umbilical hernia repair in cirrhotic patients: utility of temporary peritoneal dialysis catheter.

Umbilical herniorrhaphy in cirrhotic patients with ascites is associated with a significant morbidity, recurrence rate, and mortality and therefore is often managed expectantly. Operative repair is indicated if an ascites leak or infection develops. Surgeons must consider the management of postoperative ascites to reduce recurrence rates and complications. We present a unique method using temporary peritoneal dialysis catheter placement (PD). Eight patients with moderate to massive ascites underwent umbilical herniorrhaphy with concomitant peritoneal dialysis placement. Patients have been followed for 8 to 30 months. All patients had successful repair of their hernia with 1 recurrence at 6 months and 1 late death (14 months). Patients were able to effectively control ascites using the PD catheter at home. There were no postoperative infections. The placement of a temporary PD catheter during umbilical herniorrhaphy provides a method for effective control of ascites in patients with cirrhosis. The technique has several advantages including outpatient management during the postoperative period and for easy removal of the catheter when no longer needed.

Hepatitis C screening.

BACKGROUND: Hepatitis C screening is now recommended for all individuals born between the years 1945-1965 in addition to individuals who have high-risk factors. Although most clinicians have extensive experience with the diagnosis and treatment of the disease, they have limited experience screening for it. METHODS: We report current screening guidelines and methods. RESULTS: By identifying the disease as early as possible, screening and treatment can reduce morbidity and mortality. CONCLUSION: Screening for hepatitis C leads to the appropriate evaluation and treatment of individuals chronically infected with the hepatitis C virus and prevents the progression of liver disease to cirrhosis, hepatocellular carcinoma, and the associated morbidity and mortality. Screening for hepatitis C is also cost effective.

Global QSAR modeling of logP values of phenethylamines acting as adrenergic alpha-1 receptor agonists.

Global QSAR models predict biological response of molecular structures which are generic in particular class. A global QSAR dataset admits structural features derived from larger chemical space, intricate to model but more applicable in medicinal chemistry. The present work is global in either sense of structural diversity in QSAR dataset or large number of descriptor input. Forty phenethylamine structure derivatives were selected from a large pool (904) of similar phenethylamines available in Pubchem database. LogP values of selected candidates were collected from physical properties database (PHYSPROP) determined in identical set of conditions. Attempts to model logP value have produced significant QSAR models. MLR aided linear one-variable and two-variable QSAR models with their respective R(2) (0.866, 0.937), R(2)A (0.862, 0.932), F-stat (181.936, 199.812) and Standard Error (0.365, 0.255) are statistically fit and found predictive after internal validation and external validation. The descriptors chosen after improvisation and optimization reveal mechanistic part of work in terms of Verhaar model of Fish base-line toxicity from MLOGP, i.e. (BLTF96) and 3D-MoRSE -signal 15 /unweighted molecular descriptor calculated by summing atom weights viewed by a different angular scattering function (Mor15u) are crucial in regulation of logP values of phenethylamines.

Liver transplantation at the ochsner clinic: quality and outcomes improvement.

BACKGROUND: In 2005, the results published by the Scientific Registry of Transplant Recipients showed that Ochsner Clinic Foundation's patient and graft survival rates were statistically lower than expected, and the United Network for Organ Sharing Membership and Professional Standards Committee placed our center under peer review. METHODS: In response, patient outcomes prior to August 2005 were carefully reviewed in a transparent fashion and protocols were written to standardize treatments. We renewed the focus on patient-related outcomes and regulatory adherence and empowered frontline staff to express their views, allowing for real teamwork to develop. Multiple changes were implemented in the everyday running of the program. A quality assurance and performance improvement plan (QAPI) was initiated to improve outcomes. RESULTS: In 2012, the Ochsner liver transplant program became the largest liver transplant program in the United States by volume and in 2013 was awarded the prestigious CareChex award, acknowledging it as the number one program in terms of quality of care and outcomes for liver transplantation. CONCLUSION: The methodical application of this QAPI program achieved a remarkable transformation of the Ochsner liver transplant program and exemplifies what is possible with strong teamwork from dedicated and talented staff.

Liver transplantation at the Ochsner Clinic: programmatic expansion and outcomes improvement.

Liver transplantation has become the best and most durable treatment for both acute and chronic liver disease. Over 1400 liver transplants have been performed at the Ochsner Clinic since the first successful transplant in 1987. Since its inception, the program has gone through several changes and advancements and has become one of the largest liver transplant programs in the United States. We have helped evolve steroid sparing immunosuppression and the use of extended criteria, donor organs. Establishment of criteria for the selection of recipients for re-transplantation has resulted in better than expected short and long-term results. Our center has faced the challenge of Hurricane Katrina and overcome it. We have improved steadily in both outcomes and transplants performed. The Ochnser Clinic Liver Transplant program will continue to improve access and outcomes for all patients with liver disease.

A dose-ranging study of the efficacy and tolerability of entecavir in Lamivudine-refractory chronic hepatitis B patients.

BACKGROUND & AIMS: Entecavir is a nucleoside analogue with potent in vitro activity against lamivudine-resistant hepatitis B virus (HBV). This randomized, dose-ranging, phase 2 study compared the efficacy and safety of entecavir with lamivudine in lamivudine-refractory patients. METHODS: Hepatitis B e antigen (HBeAg)-positive and -negative patients (n = 182), viremic despite lamivudine treatment for > or =24 weeks or having documented lamivudine resistance substitutions, were switched directly to entecavir (1.0, 0.5, or 0.1 mg daily) or continued on lamivudine (100 mg daily) for up to 76 weeks. RESULTS: At week 24, significantly more patients receiving entecavir 1.0 mg (79%) or 0.5 mg (51%) had undetectable HBV DNA levels by branched chain DNA assay compared with lamivudine (13%; P < .0001). Entecavir 1.0 mg was superior to entecavir 0.5 mg for this end point (P < .01). After 48 weeks, mean reductions in HBV DNA levels were 5.06, 4.46, and 2.85 log(10) copies/mL on entecavir 1.0, 0.5, and 0.1 mg, respectively, significantly higher than 1.37 log(10) copies/mL on lamivudine. Significantly higher proportions of patients achieved normalization of alanine aminotransferase levels on entecavir 1.0, 0.5, and 0.1 mg (68%, 59%, and 47%, respectively) than on lamivudine (6%). One virologic rebound due to resistance occurred (in the 0.5-mg group). CONCLUSIONS: In HBeAg-positive and HBeAg-negative lamivudine-refractory patients, treatment with entecavir 1.0 and 0.5 mg daily was well tolerated and resulted in significant reductions in HBV DNA levels and normalization of alanine aminotransferase levels. One milligram of entecavir was more effective than 0.5 mg in this population.