Giuseppe Morelli

Cyclosporine suppresses hepatitis C virus in vitro and increases the chance of a sustained virological response after liver transplantation.

Cyclosporine is an immunosuppressive agent widely used in the management of liver transplant recipients. Cyclosporine has been shown to have antiviral activities against HIV, herpes simplex, and vaccinia viruses. The aim of this study was to determine the effect of Cyclosporine in viral clearance in the liver transplant recipients during therapy with combination of interferon and ribavirin, and to determine the anti‐viral potential of Cyclosporine in vitro. Immunosuppression consisted of either Cyclosporine or Tacrolimus‐based therapy. Both groups received therapy with interferon and ribavirin for 48 weeks when evidence of progressive histologic disease was determined. We found that subjects on Cyclosporine‐based immunosuppression (n = 56) had a higher sustained virological response of 46% compared to 27% in the patients on Tacrolimus‐based therapy (n=59, P = 0.03). In vitro studies were performed to evaluate the antiviral effect of Cyclosporine in the replicon system. These studies showed that Cyclosporine inhibits hepatitis C viral replication in a dose‐dependent manner. Combination of Cyclosporine with interferon showed additive effect, and its function is independent of interferon signaling pathways. In conclusion, Cyclosporine may offer an advantage to Tacrolimus in those patients undergoing interferon‐based therapy and should be studied in a prospective randomized trial. Liver Transpl 12:51–57, 2006.

Effectiveness of Simeprevir Plus Sofosbuvir, with or Without Ribavirin, in Real-World Patients with HCV Genotype 1 Infection

BACKGROUND & AIMS The interferon-free regimen of simeprevir plus sofosbuvir was recommended by professional guidelines for certain patients with hepatitis C virus (HCV) genotype 1 infection based on the findings of a phase 2 trial. We aimed to evaluate the safety and efficacy of this regimen in clinical practice settings in North America. METHODS We collected demographic, clinical, and virologic data, as well as reports of adverse outcomes, from sequential participants in HCV-TARGET--a prospective observational cohort study of patients undergoing HCV treatment in routine clinical care settings. From January through October 2014, there were 836 patients with HCV genotype 1 infection who began 12 weeks of treatment with simeprevir plus sofosbuvir (treatment duration of up to 16 weeks); 169 of these patients received ribavirin. Most patients were male (61%), Caucasian (76%), or black (13%); 59% had cirrhosis. Most patients had failed prior treatment with peginterferon and ribavirin without (46%) or with telaprevir or boceprevir (12%). The primary outcome was sustained virologic response (SVR), defined as the level of HCV RNA below quantification at least 64 days after the end of treatment (beginning of week 12 after treatment--a 2-week window). Logistic regression models with inverse probability weights were constructed to adjust for baseline covariates and potential selection bias. RESULTS The overall SVR rate was 84% (675 of 802 patients, 95% confidence interval, 81%-87%). Model-adjusted estimates indicate patients with cirrhosis, prior decompensation, and previous protease inhibitor treatments were less likely to achieve an SVR. The addition of ribavirin had no detectable effects on SVR. The most common adverse events were fatigue, headache, nausea, rash, and insomnia. Serious adverse events and treatment discontinuation occurred in only 5% and 3% of participants, respectively. CONCLUSIONS In a large prospective observational cohort study, a 12-week regimen of simeprevir plus sofosbuvir was associated with high rates of SVR and infrequent treatment discontinuation. ClinicalTrials.gov: NCT01474811.

Pilot study: fenofibrate for patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid

Aliment Pharmacol Ther 2011; 33: 235–242

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

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 μg/day and RBV, and 242 received CIFN 15 μg/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 μg group and 10.7% (26/242) in the 15 μg group. In the intent‐to‐treat analysis, SVR rates were higher among patients with a >2‐log10 decrease in hepatitis C virus RNA during prior PEG‐IFN/RBV therapy: 11% (4/38) in the 9 μg group and 23% (7/31) in the 15 μg group. Among patients with lower baseline fibrosis scores (F0‐F3), SVR rates were 7.8% (15/192) in the 9 μg group and 13.1% (23/175) in the 15 μg group. In this same group of patients (F0‐F3), if a >2‐log10 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 μg and 15 μg 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. (HEPATOLOGY 2009.)

The natural history of hepatitis C cirrhosis after liver transplantation

Hepatitis C after liver transplantation leads to graft cirrhosis in up to 30% of patients within 5 years, but limited data exist regarding the clinical course of cirrhosis after transplantation. The aims of this study were to report the natural history of hepatitis C cirrhosis after liver transplantation and to identify risk factors for decompensation and survival. Hepatitis C patients underwent protocol liver biopsies yearly after liver transplantation. After cirrhosis was identified by biopsy, the outcomes of interest were the development of decompensation, death, or retransplantation for hepatitis C. Kaplan‐Meier and Cox regression analysis was used to determine survival and risk factors for decompensation and mortality. Out of 502 liver transplants performed for hepatitis C, 88 patients (18%) had cirrhosis within 3.7 years. Seventy‐one patients were compensated at diagnosis. The cumulative probability of decompensation 1 year after cirrhosis was 30%. A Model for End‐Stage Liver disease score ≥ 16 was predictive of decompensation and poor survival, whereas successful interferon treatment was found to reduce this risk (relative risk = 0.05). Once decompensation occurred, 1‐year survival was 46%. In conclusion, the results confirm an accelerated natural history of hepatitis C cirrhosis after liver transplantation and demonstrate poor survival after decompensation. The Model for End‐Stage Liver Disease can stratify risk for decompensation and survival, whereas successful antiviral therapy may be protective. Liver Transpl 15:1063–1071, 2009.

Rapid-sequence endoscopic management of posttransplant anastomotic biliary strictures

BACKGROUND Post-liver-transplant anastomotic biliary strictures generally have been managed through ERCP with gradual balloon dilation and placement of multiple stents over an extended period of time. OBJECTIVE Our purpose was to evaluate the long-term outcome of rapid sequence dilation and to shorten the duration of stenting as a therapy for anastomotic biliary strictures. DESIGN Prospective case series. SETTING Academic tertiary referral center. INTERVENTIONS ERCP with rapid-sequence balloon dilation of post-liver-transplant anastomotic biliary strictures followed by stenting with multiple stents over a short time period. MAIN OUTCOME MEASUREMENT Long-term anastomotic stricture resolution. RESULTS Thirty-eight patients were prospectively enrolled into a standardized ERCP treatment protocol. The mean number of ERCPs per patient was 3.4 (range 2-6), the mean number of maximum stents inserted was 2.5 (range 1-6), and the mean total stenting period was 107 days (range 20-198 days); the mean follow-up time from completion of the endoscopic therapy was 360 days (range 140-1347 days). Long-term stricture resolution was achieved in 33 of the 38 (87%) patients. LIMITATIONS Lack of control group, relatively small patient population. CONCLUSIONS Accelerated dilation and shorter total length of stenting leads to long-term success in the majority of patients with post-liver-transplant anastomotic biliary strictures.

The combination of sorafenib with transarterial chemoembolisation for hepatocellular carcinoma

Aliment Pharmacol Ther 2011; 34: 205–213

Ledipasvir‐sofosbuvir plus ribavirin for patients with genotype 1 hepatitis C virus previously treated in clinical trials of sofosbuvir regimens

Patients who fail to achieve sustained virological response (SVR) after treatment with sofosbuvir (SOF) plus ribavirin (RBV) with or without pegylated interferon (Peg‐IFN) do not have established retreatment options. We conducted an open‐label trial to assess the efficacy and safety of ledipasvir (LDV)‐SOF plus RBV in patients with genotype 1 hepatitis C virus (HCV) who did not achieve SVR after treatment in phase II and III trials of SOF regimens. We enrolled 51 patients at 24 sites in the United States. All patients received the fixed‐dose combination tablet of LDV‐SOF once‐daily plus weight‐based RBV (1,000 or 1,200 mg/day) for 12 weeks. The efficacy endpoint was the proportion of patients with SVR 12 weeks after discontinuation of therapy (SVR12). Of the 51 patients enrolled, 25 (49%) had previously received SOF plus Peg‐IFN‐RBV, 20 (39%) had received SOF‐RBV, 5 (10%) had received SOF placebo plus Peg‐IFN‐RBV, and 1 (2%) received GS‐0938 monotherapy. Fourteen (27%) had compensated cirrhosis at baseline, and 47 (92%) had non‐CC interleukin‐28B genotypes. SVR12 was achieved by 50 of the 51 patients (98%) treated. Among the 45 patients who received SOF in earlier treatment, 44 (98%) achieved SVR12. The only patient who did not achieve SVR12 was a patient with genotype 3a HCV who had been incorrectly genotyped as 1a in the previous study. Given the high rates of SVR12, no differences among patient subgroups were discernible. Of 51 patients, 41 (80%) experienced at least one adverse event (AE), but most events were mild to moderate in severity. The most common AEs were fatigue, headache, and diarrhea. One patient discontinued treatment because of an unrelated AE (bipolar disorder). Conclusion: Twelve weeks of LDV‐SOF plus RBV was an effective and safe treatment for patients who have not achieved SVR with earlier regimens that included SOF. (Hepatology 2015;61:1793–1797)

Short Recovery Time After Percutaneous Liver Biopsy: Should We Change Our Current Practices?

BACKGROUND & AIMS Percutaneous liver biopsy is the gold standard in the diagnosis and staging of a wide variety of hepatic disorders. Complications, post-procedure monitoring, and recovery time have limited the ability for liver biopsies to be performed in a busy gastroenterology community practice. The aim of this study was to determine whether ambulatory patients requiring percutaneous liver biopsy can be safely discharged after a short recovery time period. METHODS All ambulatory patients undergoing a percutaneous liver biopsy at the University of Florida between February 1995 and June 2004 were evaluated in this study. A 15-gauge Jamshidi needle was used after percussion (before February 2002) or ultrasound guidance (starting February 2002). Major complications were defined as those events that required either immediate or delayed hospitalization or resulted in death within 2 weeks after the liver biopsy. RESULTS Three thousand two hundred fourteen outpatient liver biopsies were performed at our institution from March 1995 to June 2004. During this time, our recovery time was gradually decreased from 6 hours before 1997 to 1 hour in 2002. The majority of the complications occurred within 1 hour of the observation period or within 24 hours after discharge. The major complication rate was < or =1.7%, regardless of the observation period. CONCLUSIONS A shorter observation time after ambulatory percutaneous liver biopsy is safe and might facilitate the physicians ability to optimally utilize procedural space and ancillary staff in a busy ambulatory care unit.

Using an immune functional assay to differentiate acute cellular rejection from recurrent hepatitis C in liver transplant patients.

In transplant recipients transplanted for hepatitis C, presentation of abnormal transaminases can herald the presentation of recurrent hepatitis C, cellular rejection, or both. Given the sometimes ambiguous histology with these 2 entities, the ability to distinguish them is of great importance because misinterpretation can potentially affect graft survival. We used an immune functional assay to help assess the etiology of abnormal liver function test results in liver transplant recipients. Blood samples for the immune functional assay were taken from 42 recipients prospectively at various times post‐transplant and compared with clinical and histologic findings. In patients whose liver biopsy showed evidence of cellular rejection, the immune response was noted to be very high, whereas in those with active recurrence of hepatitis C, the immune response was found to be very low. This finding was found to be statistically significant (P < 0.0001). In those patients in whom there was no predominant histologic features suggesting 1 entity over the other, the immune response was higher than in those with aggressive hepatitis C but lower than in those with cellular rejection. In conclusion, these data show the potential utility of the ImmuKnow assay as a means of distinguishing hepatitis C from cellular rejection and its potential usefulness as a marker for outlining the progression of hepatitis C. Liver Transpl 15:216–222, 2009.