Outcomes following liver transplantation from HCV-seropositive donors to HCV-seronegative recipients.

BACKGROUND & AIMS: Grafts from HCV-seropositive donors can now be considered for liver transplantation (LT) owing to the advent of direct-acting antivirals (DAAs). We report on our multicenter experience of transplanting liver grafts from HCV-seropositive donors into HCV-seronegative recipients. METHODS: This is a prospective multicenter observational study evaluating outcomes in adult HCV-seronegative LT recipients who received grafts from HCV-seropositive donors in 3 US centers. RESULTS: From 01/18 to 09/19, 34 HCV-seronegative LT recipients received grafts from HCV-seropositive donors (20 HCV-viremic and 14 non-viremic). Seven grafts were from cardiac-dead donors. The median MELD-Na score at allocation was 20. Six recipients underwent simultaneous liver-kidney transplant and 4 repeat LT. No recipient of an HCV-non-viremic graft developed HCV viremia. All 20 patients who received HCV-viremic grafts had HCV viremia confirmed within 3 days after LT. DAA treatment was started at a median of 27.5 days after LT. Median pre-treatment viral load was 723,000 IU/ml. All (20/20) patients completed treatment and achieved SVR12. Treatment was well tolerated with minimal adverse events. One patient developed HCV-related acute membranous nephropathy that resulted in end-stage kidney disease, despite achieving viral clearance. This patient died due to presumed infectious complications. A recipient of an HCV-non-viremic graft died with acute myocardial infarction 610 days post LT. CONCLUSIONS: Transplantation of liver grafts from HCV-seropositive donors into HCV-seronegative recipients resulted in excellent short-term outcomes. Antiviral therapy was effective and well tolerated. Careful ongoing assessment and prompt initiation of antiviral therapy are recommended. Longer term follow-up in carefully conducted clinical trials is still required to confirm these results. LAY SUMMARY: This study shows that livers from donors exposed to HCV expand the donor pool and can be used safely in patients who are seronegative for hepatitis C infection. Treatment, initiated early post transplantation, is effective and resulted in cure in all patients.

Exogenous copper exposure causing clinical wilson disease in a patient with copper deficiency.

BACKGROUND: Human Swayback is a disease characterized by acquired copper deficiency which primarily manifests as myeloneuropathy. Common causes include malabsorptive disorders, gastric surgery, total parenteral nutrition and excessive zinc intake. In contrast, copper supplementation should be closely monitored as excessive doses can lead to acute intoxication and in chronic cases, cirrhosis. Copper derangements are rare, however it is important to consider them due to potential severe complications. CASE PRESENTATION: We present a middle-aged man who had been previously diagnosed with Human Swayback after presenting with various neurological symptoms. The patient was subsequently placed on copper supplementation. A decade later, he was referred to our hospital for liver transplant evaluation due to new diagnosis of decompensated end-stage liver disease after an abdominal surgery. His initial workup was suggestive of Wilson disease-subsequent ATP7B gene was negative. Ultimately, the patient underwent liver transplantation; liver explant was significant for a copper dry weight concentration of 5436 mcg/g. CONCLUSIONS: Human Swayback is a very rare copper-related disease which deserves awareness due to its potential irreversible health effects in the human body. Additionally, in patients who require copper supplementation, serial levels should be monitored to ensure adequate copper levels.

Total body weight loss of ≥ 10 % is associated with improved hepatic fibrosis in patients with nonalcoholic steatohepatitis.

BACKGROUND: Given the rising epidemics of obesity and metabolic syndrome, nonalcoholic steatohepatitis (NASH) is now the most common cause of liver disease in the developed world. Effective treatment for NASH, either to reverse or prevent the progression of hepatic fibrosis, is currently lacking. AIM: To define the predictors associated with improved hepatic fibrosis in NASH patients undergoing serial liver biopsies at prolonged biopsy interval. METHODS: This is a cohort study of 45 NASH patients undergoing serial liver biopsies for clinical monitoring in a tertiary care setting. Biopsies were scored using the NASH Clinical Research Network guidelines. Fibrosis regression was defined as improvement in fibrosis score ≥1 stage. Univariate analysis utilized Fisher's exact or Student's t test. Multivariate regression models determined independent predictors for regression of fibrosis. RESULTS: Forty-five NASH patients with biopsies collected at a mean interval of 4.6 years (±1.4) were included. The mean initial fibrosis stage was 1.96, two patients had cirrhosis and 12 patients (26.7 %) underwent bariatric surgery. There was a significantly higher rate of fibrosis regression among patients who lost ≥10 % total body weight (TBW) (63.2 vs. 9.1 %; p = 0.001) and who underwent bariatric surgery (47.4 vs. 4.5 %; p = 0.003). Factors such as age, gender, glucose intolerance, elevated ferritin, and A1AT heterozygosity did not influence fibrosis regression. On multivariate analysis, only weight loss of ≥10 % TBW predicted fibrosis regression [OR 8.14 (CI 1.08-61.17)]. CONCLUSION: Results indicate that regression of fibrosis in NASH is possible, even in advanced stages. Weight loss of ≥10 % TBW predicts fibrosis regression.

Explanted liver inflammatory grade predicts fibrosis progression in hepatitis C recurrence.

UNLABELLED: Factors present prior to liver transplantation (LT) that predict fibrosis progression in recurrent hepatitis C infection (HCV) after LT would be important to identify. This study sought to determine if histologic grade of HCV in the explant predicts fibrosis progression in recurrent HCV. The clinical and histologic data of all 159 patients undergoing their first LT for HCV at our center from 1998 to 2001 were retrospectively reviewed with follow-up through June 2008. Twenty-five cases were excluded for: non-HCV-related graft loss <90 days (19), recidivism (4), or unavailable explant or follow-up biopsies (2). A single pathologist scored (Ishak) explants in a blinded fashion. Patients were grouped by explant inflammatory grade ≤ 4 (group1) and >4 (group 2). Prospectively scored liver biopsies (protocol months 1 and 4, annually, and as indicated clinically) were reviewed for development of advanced fibrosis (bridging or cirrhosis). Cox proportional hazard regression was used to analyze the association of explant grade, donor, viral and LT factors with progression to advanced fibrosis. The groups were well-matched for patient, viral, donor, and transplant factors. Five-year advanced fibrosis-free survival in group 1 versus group 2 was 63% versus 28%, P < 0.001. Explant grade >4 was associated with increased HCV-related graft loss at 1 (6% versus 3%) and 5 (36% versus 14%) years post-LT (P = 0.003). On univariate and multivariate Cox regression analysis, predictors of advanced fibrosis were explant grade >4 (hazard ratio [HR] = 3.3, 95% confidence interval [CI] = 1.9-5.6, P < 0.001) donor age >50 (HR = 3.3, 95% CI = 1.9-5.7, P < 0.001) and viral load at LT of >158,730 IU/mL (HR = 1.8, 95% CI = 1.05-3.1, P = 0.03). CONCLUSION: Explant histologic grade can identify patients requiring more aggressive monitoring and intervention for HCV recurrence post-LT.

Improving graft survival for patients undergoing liver transplantation.

Liver transplant (LT) outcomes are reported to be improving in non-HCV recipients but not for those infected with HCV. Our aim was to evaluate graft survival and predictors of outcome in HCV and non-HCV patients before and after 2003. Patients with primary LT between February 1, 1998, and December 31, 2005, were included. Patients were divided into Era 1 (1998-2002) and Era 2 (2003-2005) with follow-up through May 31, 2009. Graft survival was compared for HCV, non-HCV, and all patients. There was significant improvement in graft survival in Era 2 for HCV patients. Graft survival in Era 2 of HCV patients was equivalent to non-HCV patients. The most significant improvement between eras was in outcomes of grafts from donors ≥60 yr with three-yr graft survival 58.6 (51.3-65.9) vs. 75.4 (68.9-81.9), p = 0.002. The use of donors ≥60 did not change between eras: 31% vs. 34%; however, utilization in HCV recipients decreased from 36% to 3% (p < 0.001). In conclusion, graft survival of HCV patients has improved significantly since 2003 and was comparable to non-HCV patients up to three yr. The change in management of donor organs into HCV and non-HCV patients likely contributed to this outcome.

Direct-Acting Antiviral Therapy in Liver Transplant Patients With Hepatocellular Carcinoma and Hepatitis C.

Direct-acting antivirals (DAA) are highly effective for the treatment of hepatitis C (HCV), although there are limited data on the safety and efficacy of DAA therapy in hepatitis C-positive individuals awaiting liver transplantation for hepatocellular carcinoma (HCC). METHODS: We conducted a retrospective cohort study of HCV-positive patients who underwent liver transplantation for HCC at 3 liver transplant centers across the United States from 2014 to 2017 with follow-up to July 2018. Transplant recipients who received DAA before transplant were compared with those who did not (DAA naive) for posttransplant HCC recurrence rate, sustained virological response (SVR), allograft failure, and death using Kaplan-Meier analysis and Cox proportional hazard models. RESULTS: A total of 171 HCV-HCC transplant recipients (99 pretransplant DAA; 72 DAA naive controls) were included, with a median follow-up of 24 months. The overall posttransplant HCC recurrence rate was 9% (15/171). Pretransplant DAA was not associated with HCC recurrence (5% versus 14%; P = 0.07), graft failure (7% versus 3%; P = 0.21), or death (12% versus 19%; P = 0.19) as compared with DAA naive patients. SVR rates were significantly lower (P < 0.01) with pretransplant DAA (75%, 39/52) than posttransplant DAA (97%, 59/61) therapies. Those who received pretransplant DAA and those who did not were not statistically different in age, gender, alpha fetal protein levels, model for end-stage liver disease scores, or transplant wait time. CONCLUSIONS: Pretransplant DAA for HCV was not associated with an increased risk of posttransplant HCC recurrence, though pretransplant DAA had lower efficacy than posttransplant DAA in HCV-HCC transplant recipients.

HCV recurrence in HIV-infected patients after liver transplant.

Patients coinfected with hepatitis C virus (HCV) and HIV undergoing liver transplantation (LT) are at risk of early, aggressive HCV recurrence. This study investigates the use of frequent protocol-driven biopsies to identify HCV recurrence post LT in coinfected patients. Five consecutive HIV/HCV-coinfected patients underwent LT. Liver biopsies were obtained post LT at 1 hour; days 7, 120, and 365; then annually; and as clinically indicated. Stage 2 (Ishak) or higher fibrosis occurred in 4 of the 5 patients by 60, 120, 270, and 365 days. Two patients died of HCV recurrence and liver failure at 6 and 35 months post LT. Three patients survived more than 4 years after LT, 2 having sustained virologic responses to anti-HCV treatment. Another has histologic recurrence not responding to treatment. Hepatitis C virus recurrence can be rapid and aggressive after LT in HIV-coinfected patients. Serial biopsies identify recurrence early, allowing for prompt initiation of treatment.

Hepatitis C Testing and Liver Fibrosis Predictors in the Birth Cohort of a Primary Care Practice.

OBJECTIVE: To determine the prevalence of and risk factors for advanced fibrosis in patients born from 1945 through 1965 (birth cohort) who underwent testing for hepatitis C virus (HCV). PATIENTS AND METHODS: Data were extracted from the electronic health record of all patients receiving primary care at a single academic institution who underwent HCV testing between September 8, 2010, and March 5, 2018. The birth cohort patients were the primary focus of the study. Fibrosis 4 (FIB-4) and aspartate aminotransferase to platelet ratio index (APRI) scores were calculated to screen for fibrosis. RESULTS: During the study period, 7097 birth cohort patients had HCV antibody testing, 3462 (48.8%) of whom were men, 6435 (91.0%) were white, 1028 (14.5%) had diabetes mellitus, 2,034 (36.5%) had an alanine aminotransferase (ALT) level greater than 30 U/L, and 2,396 (34.2%) had body mass index of 30 kg/m2 or greater. Hepatitis C virus antibody was present in 124 (1.7%), 33 (26.6%) of whom had HCV viremia. Estimated prevalence of METAVIR [Meta-analysis of Histological Data in Viral Hepatitis] stage 4 fibrosis was 4.1% (180 of 4433) by a FIB-4 score of 3.25 or greater and 4.3% (204 of 4763) by an APRI score greater than 1.0. The odds ratio (OR) for fibrosis, determined by APRI, was significant for HCV RNA positivity (OR, 15.98; 95% CI, 7.23-35.32; P<.001), diabetes mellitus (OR, 1.98; 95% CI, 1.40-2.79; P<.001), and ALT value greater than 30 U/L (OR, 15.07 U/L; 95% CI, 9.27-24.52 U/L; P<.001) but not for body mass index of 30 kg/m2 or greater (OR, 0.77; 95% CI, 0.56-1.06; P=.11). CONCLUSION: Hepatitis C virus viremia, diabetes mellitus, and elevated ALT levels were associated with increased odds for development of fibrosis. In addition to HCV testing, diabetes mellitus and elevated ALT level are potential parameters to use for recommending noninvasive testing for fibrosis.

Safety and antiviral activity of albinterferon alfa-2b in prior interferon nonresponders with chronic hepatitis C.

BACKGROUND & AIMS: Pegylated interferon alfa-2a/2b is used in combination with ribavirin to treat patients with chronic hepatitis C (CHC), although many do not achieve a sustained virologic response (SVR). Albinterferon alfa-2b, a recombinant protein consisting of interferon alfa-2b fused to human albumin, may increase drug exposure. This phase 2 study evaluated the safety/efficacy of albinterferon in CHC patients who had not responded to interferon-based regimens. METHODS: A total of 115 patients were assigned to 5 groups given 1200 microg albinterferon every 4 weeks or 900, 1200, 1500, or 1800 microg every 2 weeks, plus oral ribavirin, for 48 weeks. The primary efficacy end point was achievement of an SVR after 24 weeks. Treatment was extended to 72 weeks for 6 slow responders who were negative for hepatitis C virus RNA after 24 weeks. RESULTS: The types of adverse events were similar across groups; the overall discontinuation rate as a result of adverse events was 10.4%. Reductions in absolute neutrophil counts were less frequent in the every 4 weeks group and comparable among the every 2 weeks groups. The overall SVR rate was 17% (11% for previous nonresponders to pegylated interferon-alfa/ribavirin with genotype 1 infection). An SVR occurred in 3 of 6 slow responders by 72 weeks. The greatest reductions in hepatitis C virus RNA in nonresponders to pegylated interferon-alfa/ribavirin with genotype 1 infection were observed in the 1800-microg group. CONCLUSIONS: In patients with CHC who did not respond to interferon-based regimens, higher doses of albinterferon had significant early antiviral activity and a low incidence of adverse events, with the types of adverse events similar to those observed with interferon.

Liver transplantation and pancreatic resection: a single-center experience and a review of the literature.

Liver transplantation may occasionally be indicated in patients with unique clinical scenarios. Little is known regarding the outcomes of patients who have had a pancreatic resection prior to, in combination with, or after liver transplantation. A retrospective review of all patients undergoing liver transplantation from March 1998 to March 2008 identified 17 patients who also underwent pancreatic resection. An additional literature review was performed. Five underwent pancreatic resection prior to liver transplantation (1.7, 3.6, 3.8, 6.8, and 8.1 years), another 9 underwent pancreatic resection together with liver transplantation, and 3 underwent pancreatic resection after liver transplantation (2.2, 2.6, and 3.8 years). Indications for pancreatic resection included cholangiocarcinoma (n = 6), neuroendocrine tumor (n = 5), pancreatic cancer (n = 2), gastrointestinal stromal tumor (n = 1), periampullary adenocarcinoma (n = 1), duodenal adenomas (n = 1), and benign pancreatic mass (n = 1). Indications for liver transplantation were metastatic neuroendocrine tumor disease (n = 5), primary sclerosing cholangitis (n = 5), hepatitis C virus (n = 2), metastatic gastrointestinal stromal tumor (n = 1), Klatskin tumor (n = 1), alcohol cirrhosis (n = 1), alpha-1 antitrypsin deficiency (n = 1), and chemotherapy-induced cirrhosis (n = 1). One patient died intraoperatively, 7 patients died of tumor recurrence, 2 patients died from transplant complications, and 7 patients are still alive. Pancreatic resection-related complications included 4 pancreatic fistulas. A literature review confirmed liver transplantation/pancreatic resection-related complications. In conclusion, liver transplantation and pancreatic resection remain uncommon, and a good outcome can be achieved. Recurrence of malignant disease is the main factor limiting survival, and specific morbidity may be related to pancreatic resection and liver transplantation.

Liver transplantation using controlled donation after cardiac death donors: an analysis of a large single-center experience.

The use of donation after cardiac death (DCD) donors may provide a valuable source of organs for liver transplantation. Concerns regarding primary nonfunction (PNF) and intrahepatic biliary stricture (IHBSs) have limited the enthusiasm for their use. A retrospective analysis of 1436 consecutive deceased donor liver transplants performed between December 1998 and October 2006 was conducted. These included 108 DCD liver transplants, which were compared to 1328 transplants performed with organs from donors meeting the criteria for donation after brain death (DBD). The median follow-up was 48 months. The 1-, 3-, and 5-year patient survival and graft survival for DCD donors were 91.5%, 88.1%, and 88.1% and 79.3%, 74.5%, and 71.0%, respectively. The 1-, 3-, and 5-year patient survival and graft survival for DBD donors were 87.3%, 81.1%, and 77.2% and 81.6%, 74.7%, and 69.1%, respectively. Patient survival and graft survival were not significantly different between DCD donors less than 60 years old, DCD donors greater than 60 years old, and DBD donors. Causes of graft loss included IHBSs (n = 9), PNF (n = 4), recurrent hepatitis C virus (n = 4), hepatic artery thrombosis (n = 1), rejection (n = 2), and patient death (n = 13). Contrary to previously published data, excellent long-term patient survival and graft survival can be obtained with DCD allografts, and in our experience, they are equivalent to those obtained from DBD allografts.

Dual hepatitis virus infections in liver transplant: case report and a review of the literature.

BACKGROUND: Liver transplantation (LT) using grafts from anti-HBVcore antibody-positive (anti-HBVcAB+) donors carry risk for development of hepatitis B virus (HBV) infection. The long-term course of hepatitis C virus (HCV) patients receiving anti-HBVcAB+ grafts is poorly understood. PATIENTS AND METHODS: A patient with chronic hepatitis C received an anti-HBVc+ graft and developed de novo hepatitis B after four months. We describe the 14 HCV patients who received antiHBVc+ grafts and the condition of disease. RESULTS: Hepatitis B was treated successfully with lamivudine. One year later, breakthrough infection developed with a lamivudine-resistant mutant. Addition of adefovir led to HBV surface antigen to surface antibody seroconversion after two yr, which was maintained long term. Antiviral therapy was discontinued. Liver biopsy revealed minimal histologic changes up to eight yr post-LT. Survival of 14 recipients of antiHBVc+ allografts and 180 recipients of antiHBVc-negative grafts was equal (minimum follow up of five yr). Liver biopsies at four yr showed grade 0/1 and stage 0/1 in >70%; only two patients showed bridging fibrosis. A literature review of dual hepatitis virus infection revealed an overall milder course of hepatitis post-LT. CONCLUSION: The outcome of HCV patients receiving anti-HBc+ grafts is good and may be associated with a milder course of recurrent HCV.

Long-term outcomes of donation after cardiac death liver allografts from a single center.

Organ shortage continues to be a major challenge in transplantation. Recent experience with controlled non-heart-beating or donation after cardiac death (DCD) are encouraging. However, long-term outcomes of DCD liver allografts are limited. In this study, we present outcomes of 19 DCD liver allografts with follow-up >4.5 years. During 1998-2001, 19 (4.1%) liver transplants (LT) with DCD allografts were performed at our center. Conventional heart-beating donors included 234 standard criteria donors (SCD) and 214 extended criteria donors (ECD). We found that DCD allografts had equivalent rates of primary non-function and biliary complications as compared with SCD and ECD. The overall one-, two-, and five-yr DCD graft and patient survival was 73.7%, 68.4%, and 63.2%, and 89.5%, 89.5%, and 89.5%, respectively. DCD graft survival was similar to graft survival of SCD and ECD in non hepatitis C virus (HCV) recipients (p > 0.370). In contrast, DCD graft survival was significantly reduced in HCV recipients (p = 0.007). In conclusion, DCD liver allografts are durable and have acceptable long-term outcomes. Further research is required to assess the impact of HCV on DCD allograft survival.

Serum fibrosis markers can predict rapid fibrosis progression after liver transplantation for hepatitis C.

Although recurrent hepatitis C virus (HCV) after liver transplantation (LT) is universal, a minority of patients will develop cirrhosis within 5 years of surgery, which places them at risk for allograft failure. This retrospective study investigated whether 2 serum fibrosis markers, serum hyaluronic acid (HA) and YKL-40, could be used to predict rapid fibrosis progression (RFP) post-LT. These markers were compared with conventional laboratory tests, histological assessment, and hepatic stellate cell activity (HSCA), a key step in fibrogenesis, as assessed by immunohistochemical staining for alpha-smooth muscle actin. Serum and protocol liver biopsy samples were obtained from 46 LT recipients at means of 5 +/- 2 (biopsy 1) and 39 +/- 6 (biopsy 2) months post-LT, respectively. RFP was defined as an increase in the fibrosis score >or= 2 from biopsy 1 to biopsy 2 (a mean interval of 33 +/- 6 months). The ability of parameters at biopsy 1 to predict RFP was compared with the areas under receiver operating characteristic curves (AUROCs). Of the 46 subjects, 15 developed RFP. Serum HA and YKL-40 performed significantly better than conventional parameters and HSCA in predicting RFP post-LT for HCV at biopsy 1, with AUROCs of 0.89 and 0.92, respectively. The accuracy of serum HA >or= 90 microg/L and YKL-40 >or= 200 microg/L in predicting RFP at biopsy 1 was 80% and 96%, respectively. In conclusion, we found that elevated levels of serum HA and YKL-40 within the first 6 months after LT accurately predicted RFP. Larger studies evaluating the role of serum HA and YKL-40 in post-LT management are warranted.

Patient selection for liver transplant: 1-year experience with 555 patients at a single center.

Liver transplant (LT) has revolutionized the management of end-stage liver disease in the past 2 decades. The institution of the Model for End-Stage Liver Disease scoring system for organ allocation has de-emphasized recipient waiting time, but its effect on patients' referral to liver transplant centers is unclear. The aim of this retrospective study was to analyze the outcome of patients referred for liver transplant in a 12-month period (January 1, 2005, through December 31, 2005) after the institution of the new scoring system. During the study period, 555 patients were presented 605 times to the Liver Transplant Selection Committee. Of the 295 patients initially denied LT, 150 patients (51%) were denied because they were considered too early, 29 (10%) because their tumor did not meet institutional criteria, 72 (24%) because of concomitant psychosocial issues, and 44 (15%) because of comorbid conditions. Patients considered too early and those with psychosocial reasons for denial were often re-presented and listed for LT. Our findings suggest that patients could benefit from early referral to an LT center, even if they are initially denied listing, because management of end-stage renal disease could be initiated and psychosocial issues could be addressed. Referring physicians and transplant centers need to develop a strategy to ensure optimal timing of referrals for LT.

Transmission of viral disease to the recipient through the donor liver.

PURPOSE OF REVIEW: Morbidity and mortality after liver transplantation continue to be significantly influenced by infectious complications. A particular concern is transmission of pathogens through the graft, which may cause significant disease in the recipient. RECENT FINDINGS: For frequently transmitted herpes viruses with high seroprevalence such as cytomegalovirus, Epstein-Barr virus and human herpes viruses 6 and 7, significance, diagnosis, spectrum of disease in the recipient, prophylaxis and therapy are well established. Less is known about rare viruses such as West Nile virus, rabies virus, human choriomeningitis virus, human herpes virus 8 and human T-cell lymphoma 1, which are in many cases fatal. A plenitude of other viruses that potentially can be transmitted with a donor liver may exist, for which no detailed information is currently available. Grafts from anti-hepatitis B virus core antibody positive donors can be safely used when using lamivudine/hepatitis B immunoglobulin prophylaxis; hepatitis C virus positive organs should be given to hepatitis C virus positive individuals only. SUMMARY: With the utilization of increasingly extended criteria donors, the risk for transmission of viruses with the graft may become a more common complication. These viruses will include rare and new pathogens and testing donors for these viruses may become necessary.

Modulation of interferon-specific gene expression by albumin-interferon-alpha in interferon-alpha-experienced patients with chronic hepatitis C.

Albumin-interferon-alpha (alb-IFN) is a novel recombinant protein derived from IFN-alpha2b genetically fused to human albumin. The resulting single polypeptide combines in one molecule the antiviral properties of IFN-alpha with the long serum half-life of albumin. IFN-mediated biological responses stem from the engagement of IFN-alpha with its target receptor and subsequent modulation of IFN-specific gene (ISG) expression. To evaluate the pharmacodynamics of alb-IFN during the Phase I/II study conducted in patients with chronic hepatitis C (CHC) who had previously failed IFN-alpha-containing regimens, ISG induction was evaluated in peripheral blood and compared with antiviral response. Whole blood was obtained at day 0, day 7 and day 28 from 21 patients enrolled in the higher dose (500-900 microg) alb-IFN cohort, who received two injections on day 0 and day 14. Taqman real-time PCR was used to assess candidate ISG expression. There was sustained induction on day 7 and day 28 of the ISG's OAS1, IRF-7, IFI44 and IFI27. Although all patients showed a molecular response to alb-IFN, individual variability in pretreatment gene expression levels and fold of modulation during treatment was observed. At day 28, induction of OAS1, IFI44 and IRF7 showed pairwise correlation in individual patients (P < 0.05). Moreover, the induction of expression at day 28, and pretreatment levels of OAS1 and IFI44 correlated with hepatitis C virus RNA reduction at day 28 (P < 0.05). In conclusion, alb-IFN demonstrated robust induction of ISG that was consistent with the response associated with an IFN-alpha.

A Phase I/II study evaluating escalating doses of recombinant human albumin-interferon-alpha fusion protein in chronic hepatitis C patients who have failed previous interferon-alpha-based therapy.

Albumin-interferon-alpha (IFN-alpha) is a novel 85.7-kDa recombinant protein consisting of IFN-alpha that is genetically fused to human serum albumin. In this Phase I/II, multicentre, open-label study, we evaluated the safety and tolerability, pharmacokinetics and pharmacodynamics of albumin-IFN-alpha in IFN-alpha-experienced patients with chronic hepatitis C. Albumin-IFN-alpha was administered in 22 escalating doses (7-900 microg) in a single injection or in two injections 14 days apart. In the 119 patients studied, there were no discontinuations because of adverse events, and albumin-IFN-alpha had a favourable safety profile at doses up to 900 microg. The most common adverse events were headache (56%), fatigue (52%), injection site erythema (38%), arthralgias (32%) and pyrexia (27%). Reduced clearance resulted in a mean elimination half-life of 159 h, which supports dosing at 2- to 4-week intervals. Induction of the IFN-specific gene OAS1 was maintained for > or = 28 days following a single injection of albumin-IFN-alpha at doses of > or = 40 microg. Dose-dependent antiviral activity was observed in this IFN-alpha-experienced study population. Antiviral activity of > or = 1.0-log reductions in HCV RNA was observed in 47% (37/78) of patients in the 120- to 900-microg cohorts and in 59% (16/27) in the 400- to 900-microg double-injection cohorts. These results support further clinical studies of albumin-IFN-alpha for the treatment of patients with chronic hepatitis C.

Effect of antiviral chemoprophylaxis on adverse clinical outcomes associated with cytomegalovirus after liver transplantation.

OBJECTIVE: To assess t he association be tweencytomegalovirus (CMV) serology of donor and recipient and adverse outcomes afterliver transplantation in the era of effective antiviral chemoprophylaxis. PATIENTS AND METHODS: We performed a retrospective cohort study of 193 consecutive patients undergoing their first liver transplantation between February 1998 and July 2000 with targeted and preemptive ganciclovir chemoprophylaxis. Patients were divided into 4 groups by CMV serology of donor and recipient: donor-/recipient-; donor-/recipient+; donor+/recipient+; and donor+/recipient-. Survival to the end points of retransplantation, death, or survival to 1 year after transplantation (whichever occurred first) was assessed. Rates of bacterial, fungal, and CMV Infection and of CMV disease were recorded and compared. RESULTS: No significant differences were observed in the rates of retransplantation, death, or survival to 1 year among the 4 groups of patients. Despite significantly higher rates of CMV infection in the donor+ groups, there were no differences in the rates of bacterial or fungal Infection or of CMV disease. Rejection occurred least frequently in the donor-/recipient- group. CONCLUSION: The adverse effects of CMV on outcomes after liver transplantation have been diminished in the era of effective antiviral chemoprophylaxis.