Rohit Satoskar

Sofosbuvir plus ledispasvir for recurrent hepatitis C in liver transplant recipients.

Hepatitis C virus (HCV) recurrence after liver transplantation (LT) is associated with worse outcomes. The combination of ledipasvir (LDV) and sofosbuvir (SOF) has been approved for HCV treatment after LT, but there are limited data on the effectiveness and safety of LDV/SOF in the “real‐world” setting. This multicenter study is the largest report to date on the effectiveness and safety of LDV/SOF in the post‐LT setting. A total of 204 patients (72% male, 68% Caucasian, 66% genotype [GT] 1a, 21% METAVIR F3‐F4, 49% treatment‐experienced) were treated with LDV/SOF. The mean duration from LT to treatment initiation was 4.8 years. The overall sustained virological response rate 12 weeks after completion of therapy (SVR12) was 96%. Patients treated with 8 or 12 weeks of LDV/SOF without RBV experienced an SVR12 rate of 100% and 96%, respectively. Calcineurin inhibitors were used in 89% of patients, and 32% of patients underwent adjustment in immunosuppression during treatment. One episode of mild rejection, responsive to an increase in immunosuppression dosage, was observed. There was no graft loss attributed to HCV treatment. Four deaths occurred unrelated to HCV treatment, and no significant serious adverse events were documented. In conclusion, SOF and LDV with or without RBV for 8, 12, or 24 weeks in post‐LT patients was effective and safe with a high SVR12 rate across a spectrum of GTs and stages of fibrosis. Liver Transplantation 22 1536–1543 2016 AASLD.

Successful isolated intestinal transplantation in sensitized recipients with the use of virtual crossmatching.

We evaluated virtual crossmatching (VXM) for organ allocation and immunologic risk reduction in sensitized isolated intestinal transplantation recipients. All isolated intestine transplants performed at our institution from 2008 to 2011 were included in this study. Allograft allocation in sensitized recipients was based on the results of a VXM, in which the donor‐specific antibody (DSA) was prospectively evaluated with the use of single‐antigen assays. A total of 42 isolated intestine transplants (13 pediatric and 29 adult) were performed during this time period, with a median follow‐up of 20 months (6–40 months). A sensitized (PRA ≥ 20%) group (n = 15) was compared to a control (PRA < 20%) group (n = 27) to evaluate the efficacy of VXM. With the use of VXM, 80% (12/15) of the sensitized patients were transplanted with a negative or weakly positive flow‐cytometry crossmatch and 86.7% (13/15) with zero or only low‐titer (≤1:16) DSA. Outcomes were comparable between sensitized and control recipients, including 1‐year freedom from rejection (53.3% and 66.7% respectively, p = 0.367), 1‐year patient survival (73.3% and 88.9% respectively, p = 0.197) and 1‐year graft survival (66.7% and 85.2% respectively, p = 0.167). In conclusion, a VXM strategy to optimize organ allocation enables sensitized patients to successfully undergo isolated intestinal transplantation with acceptable short‐term outcomes.

Evaluation of Early Null Response to Pegylated Interferon and Ribavirin as a Predictor of Therapeutic Nonresponse in Patients Undergoing Treatment for Chronic Hepatitis C

OBJECTIVES:Early viral kinetics accurately predicts sustained virological response (SVR) in genotype 1 patients with hepatitis C virus (HCV) undergoing therapy with pegylated interferon (PEG) and ribavirin (RBV). No baseline factor has a stronger predictive role. Early identification of patients unlikely to respond is equally important, allowing early treatment modification or discontinuation. The aim of this study was to determine whether 4-week null response (eNR) correlates directly with 12-week null response and inversely with SVR.METHODS:A retrospective analysis of HCV patients treated at our institution was done. Patients were classified based on a 4-week viral log decline compared with baseline: <1 log, ≥1 log, <2 log, ≥2 log, <3 log, ≥3 log without rapid virological response (RVR) and with RVR. eNR was defined as less than a 1 log change from baseline.RESULTS:A total of 159 patients had quantitative HCV-RNA PCR at treatment week 4, of whom 24% (38) experienced eNR. In all, 22 (58%) of the eNR patients were African American, 58% male, 32% cirrhotic, average age 53 years (range 36–71), 89% (33) genotype 1, and average baseline viral load was 5.9261 log (range 3.1492–7.3025). On-treatment response demonstrated failure to attain early virological response (EVR; 2-log decline at week 12) in 50% (19) and partial EVR (pEVR) in 39% (15). Three (8%) patients with eNR achieved SVR. In our patient population, eNR had 92% negative predictive value (confidence interval 83.5–100%) for SVR and was the strongest single predictor for treatment failure, including the baseline factors genotype and viral load.CONCLUSIONS:eNR is strongly associated with null response or pEVR and accurately predicts failure to attain SVR. Consideration should be made to discontinue or modify therapy in patients with eNR who receive the appropriate weight-based PEG/RBV.

Co-management Between Hospitalist and Hepatologist Improves the Quality of Care of Inpatients With Chronic Liver Disease

Background and Goals: Our institution shifted the care of patients with chronic liver disease (CLD) from Internal Medicine faculty, house staff, and consulting hepatology service to a co-managed unit staffed by academic hospitalists and hepatologists. The effect of co-management between hospitalists and hepatologists on the care of patients hospitalized with complications of CLD such as spontaneous bacterial peritonitis (SBP) is unknown. Study: A retrospective chart review of 56 adult patients admitted with CLD and SBP from July 1, 2004 to June 30, 2010 was performed. Adherence rates to current management guidelines were measured along with costs and outcomes of care. Results: Patients admitted under the 2 models of care were similar; however, they consistently underwent paracentesis within 24 hours (100% vs. 79%, P=0.013), had appropriate avoidance of fresh-frozen plasma use (75% vs. 43%, P=0.05), received albumin (97% vs. 65%, P=0.002), and were discharged on SBP prophylaxis (91% vs. 37%, P<0.001) under the co-managed model compared with the conventional model. Costs of care were similar between the 2 groups. We note a trend toward improved outcomes of care under the co-management model as measured by transfer rates to the intensive care unit, inpatient mortality, 30-day readmission, and mortality rates. Conclusions: These results support co-management between hospitalists and hepatologists as a superior model of care for hospitalized patients with SBP. Furthermore, this study adds to the growing literature indicating that efforts are needed to improve the quality of care delivered to CLD patients.

Persistent spontaneous bacterial peritonitis: a common complication in patients with spontaneous bacterial peritonitis and a high score in the model for end-stage liver disease

Objectives: Spontaneous bacterial peritonitis (SBP) is associated with a high mortality rate. After antibiotic therapy, improvement in fluid polymorphonuclear (PMN) cell count is expected within 2 days. However, our institution recognized cases unresponsive to standard treatment. Methods: To study these recalcitrant cases, we completed a retrospective chart review of patients admitted for SBP to the University of Chicago from 2002 to 2007. SBP was defined by an ascitic PMN cell count ≥250/ml. Results: Of 55 patients with SBP, 15 did not show improvement in fluid PMN cell count to below 250/ml with standard treatment, leading to a prevalence of 27%. The patients with persistent SBP were younger than those with nonpersistent SBP [mean (SD) 51.80 (9.84) compared with 58.13 (8.79); p = 0.0253]. Persistent SBP had a higher serum ascites albumin gradient (SAAG) [median (Q1, Q3) 1.85 (1.50, 2.41) compared with 1.10 (0.60, 1.60)] and a higher score in the model for end-stage liver disease (MELD) [mean (SD) 27.98 (8.09) compared with 22.22 (8.10)] than nonpersistent SBP patients; p = 0.027 and p = 0.023, respectively. In addition, persistent SBP patients were more likely to have a positive ascitic fluid culture than nonpersistent SBP patients [odds ratio (OR) (95% CI) 4.33 (1.21, 15.47); p = 0.024]. Importantly, in-hospital mortality in the persistent SBP group was 40%, compared with 22.5% in the nonpersistent SBP group [OR = 2.30 (0.64, 8.19); p = 0.20]. Conclusions: The risk of persistent SBP is nearly 40% in patients with MELD score >25, SAAG >1.5 or positive ascitic fluid culture. Furthermore, patients who develop persistent SBP tend to experience a higher mortality rate. This study underscores the importance of further examination of this vulnerable population.

Ledipasvir/sofosbuvir is effective and well tolerated in postkidney transplant patients with chronic hepatitis C virus

Patients with end‐stage renal diseases on hemodialysis have a high prevalence of hepatitis C infection (HCV). In most patients, treatment for HCV is delayed until postrenal transplant. We assessed the effectiveness and tolerance of ledipasvir/sofosbuvir (LDV/SOF) in 32 postkidney transplant patients infected with HCV. The group was composed predominantly of treatment‐naïve (75%) African American (68.75%) males (75%) infected with genotype 1a (62.5%). Most patients received a deceased donor kidney graft (78.1%). A 96% sustained viral response (SVR) was reported (27/28 patients). One patient relapsed. One patient with baseline graft dysfunction developed borderline rejection. No graft loss was reported. Six HIV‐coinfected patients were included in our analysis. Five of these patients achieved SVR 12. There were four deaths, and one of the deaths was in the HIV group. None of the deaths were attributed to therapy. Coinfected patients tolerated therapy well with no serious adverse events. Serum creatinine remained stable at baseline, end of therapy, and last follow‐up, (1.351±.50 mg/dL; 1.406±.63 mg/dL; 1.290±.39 mg/dL, respectively). In postkidney transplant patients with HCV infection with or without coinfection with HIV, a combination of LDV/SOF was well tolerated and effective.

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, Maddreys 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.

Use of immune function test in monitoring immunosuppression in liver transplant recipients

Immune function test (Immuknow™) is a measure of cell‐mediated immunity based on peripheral CD4+ T cell adenosine triphosphate activity (desired range, 225–525 ng/mL). We evaluated the role of immune function test (IFT) in monitoring and adjustment of immunosuppression in orthotopic liver transplant (OLT) recipients. A total of 289 IFTs were obtained from 171 patients from March 2007 to June 2008. Graft/patient status was classified as stable, serious infection, or malignancy. IFT levels were analyzed with duration of follow‐up after OLT, graft/patient status, and the presence of hepatitis C (HCV) infection. The mean age was 54 ± 14 yr, with 62% men. The median follow‐up was 65 (2–249) months. Mean IFT levels were significantly lower in patients who were <24 months than in those ≥24 months post‐OLT (220 ± 19.5 vs. 257 ± 11.3 ng/mL, p = 0.03). Clinically stable patients had higher IFT levels than those with serious infection or malignancy (254 ± 11.1 vs. 162.5 ± 23.9, p < 0.001). HCV‐infected patients had lower IFT levels than uninfected patients (206.7 ± 15.7 vs. 273 ± 12.0 ng/mL, p < 0.001). Immunosuppression was reduced in 58 patients with IFT levels <225 ng/mL, and 90% maintained stable graft function after a median follow‐up of 22 (1–39) months. IFT may be a useful tool in monitoring and lowering of immunosuppression in long‐term OLT recipients.

MELD: Which Patients Fall Through the Cracks?

In 2002, the use of the MELD scoring system was adopted as the primary means of determining the priority of patients listed for liver transplantation. Implementation of the MELD system has changed the face of organ allocation for livers and as a result, overall waitlist times along with pre- and post-transplant mortality for patients with significant liver disease have declined. Although the MELD accurately predicts mortality in most patients with end stage liver disease, it may not adequately risk stratify some patients who have a high risk of morbidity and mortality not reflected in the score. Automatic exception points are granted for a subset of conditions if candidates meet agreed upon criteria. However, even within this framework, there are some at risk patients who will be missed. Herein we review conditions associated with increased mortality and morbidity that are not reflected in the MELD score and reflect on the issues which arise when considering allocation of organs to these patients.

Direct-acting antiviral regimens are safe and effective in the treatment of hepatitis C in simultaneous liver-kidney transplant recipients

Hepatitis C (HCV) remains the single most common etiology of end‐stage liver disease leading to simultaneous liver/kidney transplant (SLKT) and has worse post‐transplant survival compared to non‐HCV patients. We aim to assess the effectiveness and tolerance of the all‐oral direct‐acting antiviral (DAA) agents with or without ribavirin (RBV) in the treatment of HCV recurrence post‐SLKT. Thirty‐four patients were studied retrospectively, composed predominantly of treatment‐naïve (73.5%) non‐Caucasian (61.8%) males (82.4%) infected with genotype 1a (64.7%). 94.1% reached a sustained virologic response (SVR) after 24 weeks (32/34 patients), without difference between 12 and 24 weeks of therapy. 64.7% had no clinical side effects. Three deaths occurred, all unrelated to treatment. One patient had liver rejection; tacrolimus was increased and prednisone was initiated while HCV treatment was continued and the patient ultimately achieved SVR. No liver graft losses. No kidney rejection or losses. We demonstrated that DAA combinations with or without RBV result in a remarkable SVR rate and tolerated in the majority of the studied SLKT patients. It is safe to wait to treat until post–kidney transplant and therefore increase the donor pool for these patients. Our cohort is ethnically diverse, making our results generalizable.