Mario Angelico

Isosorbide-5-mononitrate versus propranolol in the prevention of first bleeding in cirrhosis

BACKGROUND Hemodynamic studies have shown the efficacy of nitrates in reducing portal pressure in cirrhosis. We therefore studied the efficacy of isosorbide-5-mononitrate vs. propranolol in the prevention of first bleeding within a prospective controlled trial. METHODS One hundred eighteen cirrhotics with esophageal varices were blindly randomized to receive 20 mg of isosorbide-5-mononitrate three times a day (n = 57) or propranolol (n = 61) up to the maximum tolerated dose. Both groups also received ranitidine (150 mg/day). RESULTS The median follow-up was 29 months. Twenty-six patients dropped out (13 in the isosorbide group) because of poor compliance or complications unrelated to treatment. Eighteen patients died (9 in the isosorbide-treated group), 6 due to bleeding. The 1- and 2-year actuarial percentages of patients free of bleeding was 90.8% and 82.2% in the isosorbide-5-mononitrate--and 93.9% and 85.8% in the propranolol-treated groups, respectively (P = NS). These values are higher than those expected from the North Italian Endoscopic Club predicting scores. There were few major side effects in either group. The 2-year survival rate did not differ between the two groups (82.2% vs. 85.4%). CONCLUSIONS Isosorbide-5-mononitrate administered orally is a safe and effective alternative to propranolol in the prophylaxis of bleeding in cirrhosis.

A pilot study on the safety and effectiveness of immunosuppression without prednisone after liver transplantation

BACKGROUND Corticosteroids are commonly used in the immunosuppression therapy after liver transplantation, yet are associated with considerable side effects. Retrospective studies have shown that corticosteroids can be safely withdrawn from months to years after transplant. We prospectively investigated the effects of early immunosuppression without the use of corticosteroids on graft outcome and transplant complications. METHODS Forty-five patients undergoing liver transplantation were randomized to receive immunosuppression composed of cyclosporine microemulsion and azathioprine with (n=22) or without prednisone (n=23), in conventional doses. In those patients who received prednisone, this was withdrawn within 3 months after transplant. The median follow-up of survivors was 14 months (range: 6-24). The study end points were to determine graft survival and function, infectious complications, including hepatitis C virus (HCV)-RNA levels in HCV-infected recipients, acute rejection, kidney function, and metabolic complications. RESULTS Eleven deaths occurred, 6 of which were in the prednisone group. Two-year survival did not differ between patients treated with or without prednisone (70.2% vs. 78.3%, P=0.83), nor did the causes of death. No differences were observed with regard to graft function, renal function, and infectious complications. In the subset of patients who received transplants for HCV-related cirrhosis, the dynamics of virus replication HCV-RNA was faster among those treated with prednisone. The incidence and severity of acute rejection was similar in the two groups. More than 80% of acute rejections in both groups were classified as mild or moderate and underwent spontaneous resolution. Only two patients in each group had severe acute rejection requiring additional treatment with high-dose steroids. Patients receiving prednisone tended to have greater biochemical signs of cholestasis, higher serum cholesterol and glucose levels, and more frequent insulin requirement than those treated without corticosteroids. CONCLUSIONS Liver transplantation can be performed safely without using corticosteroids in the early postoperative course, and there is no need for routine aggressive steroid treatment of established acute rejections.

Sofosbuvir plus daclatasvir for post-transplant recurrent hepatitis C: Potent antiviral activity but no clinical benefit if treatment is given late

BACKGROUND We evaluated efficacy and safety of sofosbuvir and daclatasvir±ribavirin in liver transplant recipients with severe recurrent hepatitis C. METHODS Patients included in an international compassionate use programme for treatment with sofosbuvir and daclatasvir±ribavirin for 24 weeks were prospectively studied. Serum hepatitis C virus RNA was measured at treatment weeks 4, 12, and 24 and during follow-up at weeks 4, 8, and 12. RESULTS Twelve patients (3 with fibrosing cholestatic hepatitis and 9 with cirrhosis; median model for end-stage liver disease score 20) received sofosbuvir 400mg/day+daclatasvir 60mg/day, and 6 patients (50%) also received ribavirin 200-800mg/day. Nine patients completed 24 weeks of treatment (75%), and all had undetectable hepatitis C virus RNA at week 24; 3 patients died (25%, liver failure, gastrointestinal bleeding and sepsis); 4 patients experienced severe liver disease-related adverse events. Post-treatment hepatitis C virus RNA was available for 5 patients (week 8, n=2; week 4, n=3) and was undetectable in all cases. Mean Child-Pugh score and albumin level improved significantly at week 24. No changes in immunosuppressant doses were needed. CONCLUSION All-oral sofosbuvir plus daclatasvir combination shows high virological efficacy in liver transplant recipients and does not interact with immunosuppressants. All adverse events were unrelated to study drugs. These data strongly suggest that this combination must be initiated before decompensation.

HCV Genotypes Are Differently Prone to the Development of Resistance to Linear and Macrocyclic Protease Inhibitors

Background Because of the extreme genetic variability of hepatitis C virus (HCV), we analyzed whether specific HCV-genotypes are differently prone to develop resistance to linear and macrocyclic protease-inhibitors (PIs). Methods The study includes 1568 NS3-protease sequences, isolated from PI-naive patients infected with HCV-genotypes 1a (N = 621), 1b (N = 474), 2 (N = 72), 3 (N = 268), 4 (N = 54) 5 (N = 6), and 6 (N = 73). Genetic-barrier was calculated as the sum of nucleotide-transitions (score = 1) and/or nucleotide-transversions (score = 2.5) required for drug-resistance-mutations emergence. Forty-three mutations associated with PIs-resistance were analyzed (36A/M/L/G-41R-43S/V-54A/S/V-55A-Q80K/R/L/H/G-109K-138T-155K/Q/T/I/M/S/G/L-156T/V/G/S-158I-168A/H/T/V/E/I/G/N/Y-170A/T-175L). Structural analyses on NS3-protease and on putative RNA-models have been also performed. Results Overall, NS3-protease was moderately conserved, with 85/181 (47.0%) amino-acids showing <1% variability. The catalytic-triad (H57-D81-S139) and 6/13 resistance-associated positions (Q41-F43-R109-R155-A156-V158) were fully conserved (variability <1%). Structural-analysis highlighted that most of the NS3-residues involved in drug-stabilization were highly conserved, while 7 PI-resistance residues, together with selected residues located in proximity of the PI-binding pocket, were highly variable among HCV-genotypes. Four resistance-mutations (80K/G-36L-175L) were found as natural polymorphisms in selected genotypes (80K present in 41.6% HCV-1a, 100% of HCV-5 and 20.6% HCV-6; 80G present in 94.4% HCV-2; 36L present in 100% HCV-3-5 and >94% HCV-2-4; 175L present in 100% HCV-1a-3-5 and >97% HCV-2-4). Furthermore, HCV-3 specifically showed non-conservative polymorphisms (R123T-D168Q) at two drug-interacting positions. Regardless of HCV-genotype, 13 PIs resistance-mutations were associated with low genetic-barrier, requiring only 1 nucleotide-substitution (41R-43S/V-54A-55A-80R-156V/T: score = 1; 54S-138T-156S/G-168E/H: score = 2.5). By contrast, by using HCV-1b as reference genotype, nucleotide-heterogeneity led to a lower genetic-barrier for the development of some drug-resistance-mutations in HCV-1a (36M-155G/I/K/M/S/T-170T), HCV-2 (36M-80K-155G/I/K/S/T-170T), HCV-3 (155G/I/K/M/S/T-170T), HCV-4-6 (155I/S/L), and HCV-5 (80G-155G/I/K/M/S/T). Conclusions The high degree of HCV genetic variability makes HCV-genotypes, and even subtypes, differently prone to the development of PIs resistance-mutations. Overall, this can account for different responsiveness of HCV-genotypes to PIs, with important clinical implications in tailoring individualized and appropriate regimens.

A randomized controlled trial of pegylated interferon-α2a plus adefovir dipivoxil for hepatitis B e antigen-negative chronic hepatitis B

BACKGROUND Pegylated interferon (PEG-IFN)-alpha monotherapy is the current standard of care for short-term antiviral treatment of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). We aimed to assess the safety and efficacy of PEG-IFN-alpha plus adefovir dipivoxil (ADV) versus PEG-IFN-alpha monotherapy for compensated HBeAg-negative CHB. METHODS A multicentre randomized controlled trial was performed in eight outpatient hepatology/infectious disease clinics in central Italy. A total of 60 patients (67% male and median age 48 years) with biopsy-proven HBeAg-negative compensated CHB (mean alanine aminotranferase [ALT] levels 3.3 +/-3x the upper normal limit and serum hepatitis B virus [HBV] DNA 5.8 +/-0.9 log(10) IU/ml) were randomized at baseline to receive PEG-IFN-alpha2a 180 microg/week plus ADV 10 mg/day or PEG-IFN-alpha2a monotherapy for 48 weeks. Post-treatment follow-up was for 24 additional weeks. The primary end point was sustained HBV DNA suppression defined as serum HBV DNA<2,000 IU/ml after 24 weeks of post-treatment follow-up. The secondary end point was ALT normalization at the end of follow-up. RESULTS At week 48, HBV DNA was undetectable in 20/30 (67%) in the combination group versus 11/30 (37%) patients in the monotherapy group (P=0.02). ALT normalization was achieved in 17/30 (57%) versus 10/30 (30%) patients, respectively (P=0.03). At week 72, sustained virological response was achieved in 7/30 (23.3%) in the combination group versus 6/30 (20%) patients in the monotherapy group (P=0.75); 5 (16%) patients in each group dropped out because of adverse events or non-compliance. CONCLUSIONS In HBeAg-negative CHB, combination PEG-IFN-alpha2a plus ADV for 48 weeks is safe and resulted in greater on-treatment efficacy than PEG-IFN-alpha2a monotherapy. No difference in sustained virological and biochemical response rates were observed between the two treatment regimens.

Review article: hepatobiliary complications associated with total parenteral nutrition

Parenteral nutrition is often associated with hepatobiliary complications. Hepatic steatosis, intrahepatic cholestasis and biliary sludge are the most frequent. Cholestasis predominates in infants, steatosis in adults, and biliary sludge in both. Other less frequent complications are steatohepatitis and gallstones. All hepatobiliary complications are more likely to occur after extended periods of total parenteral nutrition, and are prevented by the concomitant consumption of nutrients by the enteral route. The pathogenic causes are multiple and only partially known. They include lack of gastrointestinal stimuli for biliary secretion and gall‐bladder motility, abnormalities in bile acid metabolism, the presence of sepsis, and the potentially unfavourable effects of individual components in the total parenteral nutrition formulae, including an excess of calories. Each potential mechanism and its clinical relevance is discussed in this review.

Liver Match, a prospective observational cohort study on liver transplantation in Italy: Study design and current practice of donor-recipient matching

BACKGROUND The Liver Match is an observational cohort study that prospectively enrolled liver transplantations performed at 20 out of 21 Italian Transplant Centres between June 2007 and May 2009. Aim of the study is to investigate the impact of donor/recipient matching on outcomes. In this report we describe the study methodology and provide a cross-sectional description of donor and recipient characteristics and of graft allocation. METHODS Adult primary transplants performed with deceased heart-beating donors were included. Relevant information on donors and recipients, organ procurement and allocation were prospectively entered in an ad hoc database within the National Transplant Centre web-based Network. Data were blindly analysed by an independent Biostatistical Board. RESULTS The study enrolled 1530 donor/recipient matches. Median donor age was 56 years. Female donors (n = 681, median 58, range 12-92 years) were older than males (n = 849, median 53, range 2-97 years, p < 0.0001). Donors older than 60 years were 42.2%, including 4.2% octogenarians. Brain death was due to non-traumatic causes in 1126 (73.6%) cases. Half of the donor population was overweight, 10.1% was obese and 7.6% diabetic. Hepatitis B core antibody (HBcAb) was present in 245 (16.0%) donors. The median Donor Risk Index (DRI) was 1.57 (>1.7 in 35.8%). The median cold ischaemia time was 7.3h (≥ 10 in 10.6%). Median age of recipients was 54 years, and 77.7% were males. Hepatocellular carcinoma (HCC) was the most frequent indication overall (44.4%), being a coindication in roughly 1/3 of cases, followed by viral cirrhosis without HCC (28.2%) and alcoholic cirrhosis without HCC (10.2%). Hepatitis C virus infection (with or without HCC) was the most frequent etiologic factor (45.9% of the whole population and 71.4% of viral-related cirrhosis), yet hepatitis B virus infection accounted for 28.6% of viral-related cirrhosis, and HBcAb positivity was found in 49.7% of recipients. The median Model for End Stage Liver Disease (MELD) at transplant was 12 in patients with HCC and 18 in those without. Multivariate analysis showed a slight but significant inverse association between DRI and MELD at transplant. CONCLUSIONS The deceased donor population in Italy has a high-risk profile compared to other countries, mainly due to older donor age. Almost half of the grafts are transplanted in recipients with HCC. Higher risk donors tend to be preferentially allocated to recipients with HCC, who are usually less ill and older. No other relevant allocation strategy is currently adopted at national level.

Percutaneous Cryoablation of Small Hepatocellular Carcinoma with US Guidance and CT Monitoring: Initial Experience

The purpose of this study was to retrospectively determine the safety and effectiveness of percutaneous cryoablation, monitored with computed tomography (CT) and ultrasonographic (US) guidance, for the treatment of hepatocellular carcinoma (HCC). Four patients with small HCCs underwent one percutaneous cryoablation treatment session monitored with CT and US guidance. All patients underwent pretreatment blood chemistry testing and imaging evaluation. We treated lesions with simultaneous insertion of multiple 17-G cryoprobes (two or three) and defined technical success when the extension of a visible iceball was beyond 5 mm from the tumor margin. Intralesional enhancement or tumoral size increase was defined as local progression compared with that on images obtained immediately after ablation. We evaluated complications and follow-up (at 1, 3, and 6 months). All patients survived without short- or long-term complications. Cryoablation was technically successful in all patients at the end of the procedure. During follow-up two patients developed disease recurrence. One patient developed local tumor progression on the margin of the lesion; the other, a new HCC. In the case of local tumor progression a new elevation of α-fetoprotein (αFP) levels occurred at first follow-up control. In the other case levels of αFP remained stable during the first 3 months after the procedure, then demonstrated a progressive increase in αFP levels beginning at the fourth month, without tumor evidence during CT control at 3 months. We conclude that percutaneous cryotherapy with US guidance and CT monitoring is a feasible, safe, and effective for treatment of HCC. If local ablative procedures of hepatic lesions are to be performed, percutaneous cryoablation, not laparotomic, should be discussed as an alternative therapeutic measure. Longer follow-up should provide proof of the effectiveness of this technique.

Safety of complete and sustained prophylaxis withdrawal in patients liver-transplanted for HBV-related cirrhosis at low risk of HBV recurrence

BACKGROUND & AIMS HBV reactivation after liver transplantation may be related to persistence of covalently closed circular (ccc) DNA. We investigated the safety of HBV prophylaxis withdrawal in selected HBV transplanted patients. METHODS Thirty patients transplanted 64-195months earlier (23 males, median age 56yrs), HBsAg-positive, HBeAg, and HBV-DNA negative at transplant (43% HCV/HDV co-infected), with undetectable intrahepatic total and ccc-DNA were enrolled. All patients underwent HBIg withdrawal and continued lamivudine with monthly HBsAg and HBV-DNA monitoring and sequential liver biopsies. Those with confirmed intrahepatic total and ccc-DNA undetectability 24weeks after stopping HBIg, also underwent lamivudine withdrawal and were followed-up without prophylaxis. RESULTS Twenty-five patients did not exhibit signs of HBV recurrence after prophylaxis withdrawal (median follow-up 28.7months, range 22-42). Five patients became HBsAg-positive: one early after HBIg withdrawal, the other four after HBIG and lamivudine withdrawal. None of these patients experienced clinically relevant events. In the first patient, HBIg were reinstituted with prompt HBsAg negativization. Of the other four, one remained HBsAg-positive with detectable HBV-DNA and mild ALT elevation and was successfully treated with tenofovir. In the remaining three, HBsAg positivity was transient and followed by anti-HBs seroconversion, thus no antiviral treatment was needed. CONCLUSIONS Patients with undetectable HBV viremia at transplant and no evidence of intrahepatic total and cccDNA may safely undergo cautious weaning of prophylaxis, showing low rate of HBV recurrence after a 2 year follow-up. Undetectability of intrahepatic ccc-DNA may help to identify patients at low-risk of recurrence, yet studies with longer follow-up are needed.

Low-dose hepatitis B immunoglobulin given "on demand" in combination with lamivudine: a highly cost-effective approach to prevent recurrent hepatitis B virus infection in the long-term follow-up after liver transplantation

Background. Cost of long-term prophylaxis with high-dose human hepatitis B immune globulin (HBIg) after liver transplantation is extremely high. The aim of the present study was to assess consumption rates of high (5,000 IU) and low (2,000 IU) doses of HBIg given intravenously “on demand,” and determine their cost-effectiveness compared with conventional fixed monthly schedules. Methods. The study included 11 male patients (mean age 53 years) who received transplants for hepatitis B virus (HBV)-related cirrhosis 29 to 96 months earlier, all receiving lamivudine (100 mg/day) prophylaxis. Each patient received three consecutive intravenous infusions of 5,000 IU HBIg, followed by three 2,000 IU infusions. HBIg consumption was assessed by serial measurement of serum hepatitis B surface antibody (HBsAb) titer at 2-week intervals. HBIg was readministered only when HBsAb titers dropped below 70 IU/L (i.e., “on demand”). Results. Mean HBsAb peak titers after high and low HBIg doses were 1,641±385 and 848±216 IU/L, respectively (P <0.0001). Mean time to reach an HBsAb titer less than 70 IU/L was 79.5±38.2 days versus 61.6±32.1 days, respectively (P =NS). Interindividual variation coefficients were 23±18% and 32±26% (5,000 IU and 2,000 IU, respectively). Using the on demand approach, maintenance of a protective anti-HBs titer required an average number of 4.0 (5,000 IU) and 5.6 (2,000 IU) HBIg administrations per year, respectively (P =NS). Conclusions. Individual HBIg consumption profiles are highly variable. A low-dose (2,000 IU) on demand HBIg administration schedule is highly cost-effective and provides more than 50% savings compared with conventional high-dose monthly schedules.