Antibiotic prophylaxis in variceal hemorrhage: timing, effectiveness and Clostridium difficile rates.

AIM: To investigate if antibiotics administered within 8 h of endoscopy reduce mortality or increase the incidence of Clostridium difficile infection (CDI). METHODS: A 2-year retrospective analysis of all patients who presented with first variceal hemorrhage was undertaken. The primary outcome measure was 28-d mortality. Secondary outcome measures were 28-d rebleeding rates and 28-d incidence of CDI. All patients were admitted to a tertiary liver unit with a consultant-led, 24-h endoscopy service. Patients received standard care including terlipressin therapy. Data collection included: primary and secondary outcome measures, timing of first administration of intravenous antibiotics, etiology of liver disease, demographics, endoscopy details and complications. A prospective study was undertaken to determine the incidence of CDI in the study population and general medical inpatients admitted for antibiotic therapy of at least 5 d duration. Statistical analysis was undertaken using univariate, non-parametric tests and multivariate logistic regression analysis. RESULTS: There were 70 first presentations of variceal hemorrhage during the study period. Seventy percent of cases were male and 65.7% were due to chronic alcoholic liver disease. In total, 64/70 (91.4%) patients received antibiotics as prophylaxis during their admission. Specifically, 53/70 (75.7%) received antibiotics either before endoscopy or within 8 h of endoscopy [peri-endoscopy (8 h) group], whereas 17/70 (24.3%) received antibiotics at > 8 h after endoscopy or not at all (non peri-endoscopy group). Overall mortality and rebleeding rates were 13/70 (18.6%) and 14/70 (20%), respectively. The peri-endoscopy (8 h) group was significantly less likely to die compared with the non peri-endoscopy group [13.2% vs 35.3%, P = 0.04, odds ratio (OR) = 0.28 (0.078-0.997)] and showed a trend towards reduced rebleeding [17.0% vs 29.4%, P = 0.27, OR = 0.49 (0.14-1.74)]. On univariate analysis, the non peri-endoscopy group [P = 0.02, OR = 3.58 (1.00-12.81)], higher model for end-stage liver disease (MELD) score (P = 0.02), presence of hepatorenal syndrome [P < 0.01, OR = 11.25 (2.24-56.42)] and suffering a clinical episode of sepsis [P = 0.03, OR = 4.03 (1.11-14.58)] were significant predictors of death at 28 d. On multivariate logistic regression analysis, lower MELD score [P = 0.01, OR = 1.16 (1.04-1.28)] and peri-endoscopy (8 h) group [P = 0.01, OR = 0.15 (0.03-0.68)] were independent predictors of survival at 28 d. The CDI incidence (5.7%) was comparable to that in the general medical population (5%). CONCLUSION: Antibiotics administered up to 8 h following endoscopy were associated with improved survival at 28 d. CDI incidence was comparable to that in other patient groups.

Hepatocellular carcinoma in patients with chronic hepatitis C virus infection without cirrhosis.

AIM: To investigate and characterise patients with chronic hepatitis C virus (HCV) infection presenting with hepatocellular carcinoma (HCC) in the absence of cirrhosis. METHODS: Patients with chronic hepatitis C infection without cirrhosis presenting with HCC over a 2-year period were identified. The clinical case notes, blood test results and histological specimens were reviewed to identify whether additional risk factors for the development of HCC were present. RESULTS: Six patients (five male, one female) with chronic hepatitis C infection without cirrhosis presented to a single centre with HCC over a 2-year period. Five patients were treated by surgical resection and one patient underwent liver transplantation. Evaluation of generous histological specimens confirmed the presence of HCC and the absence of cirrhosis in all cases. The degree of fibrosis of the background liver was staged as mild (n = 1), moderate (n = 4) or bridging fibrosis (n = 1). Review of the clinical case notes revealed that all cases had an additional risk factor for the development of HCC (four had evidence of past hepatitis B virus infection; two had a history of excessive alcohol consumption; a further patient had prolonged exposure to immune suppression). CONCLUSION: HCC does occur in patients with non-cirrhotic HCV infection who have other risk factors for hepatocarcinogenesis.

Telaprevir: a new hope in the treatment of chronic hepatitis C?

More than 180 million people worldwide have chronic hepatitis C (CHC) virus infection, a major cause of liver cirrhosis and its life-threatening complications including liver failure, portal hypertension, and hepatocellular carcinoma. With the current standard of care of pegylated interferon-alpha and ribavirin (PEG-IFN-alpha/RBV), the chances of sustained viral clearance or "cure" are only 40%-50% for genotype 1 infection, which is the most common genotype in western populations. Consequently, there has been a drive to develop new agents specifically targeting essential components of the viral life cycle, such as the hepatitis C virus (HCV) NS3/4A serine protease. Perhaps the most advanced HCV protease inhibitor in clinical development is telaprevir, which has been shown to improve treatment outcomes when combined with PEG-IFN-alpha/RBV in genotype 1 infection, and is currently undergoing phase 3 study. In this review, we summarize the pharmacology, pharmacokinetics, and results of phase 1 and 2 clinical trials of telaprevir, and discuss the likely role of this agent in the future management of CHC.

The case for combination antiviral therapy for chronic hepatitis B virus infection.

The treatment of hepatitis B virus (HBV) infection has been revolutionised in the past decade by the increased availability of effective antiviral agents. Many studies have shown the benefits of single agent therapy, but there is an alarming and rising rate of viral resistance, and clear evidence that viruses that harbour resistant mutations can cause liver disease and death. Current national guidelines for the treatment of HBV recommend a programme that starts with monotherapy, followed by sequential monotherapy or add-on therapy for those infections in which mutations have arisen. Very few studies starting with combination therapy have been undertaken, so there is little evidence of the clinical benefit of this approach to treatment. The studies that have been done have been short term and have concentrated on clinical parameters rather than virological resistance, which is likely to be the key determinant in the longer term. We argue that we should not wait for the evidence to use combination therapy for the treatment of HBV, since such trials may never be done and it would take several years for a benefit to become apparent. In the meantime, multidrug-resistant strains continue to hinder HBV control.

Hepatocyte-specific gene expression from integrated lentiviral vectors.

BACKGROUND: For many applications, efficient gene therapy will require long-term, organ-specific therapeutic gene expression. Lentiviral vectors based on HIV-1 are promising gene delivery vehicles due to their ability to integrate transgenes into non-dividing cells. Many experimental vectors express transgenes under the control of the cytomegalovirus (CMV) immediate-early gene promoter. Although this promoter directs strong gene expression in vitro, it may be shut off rapidly in vivo. This study explores the potential of HIV-1-based vectors to transduce hepatocytes and compares gene expression from different promoters in integrated vectors. METHODS: HIV-1-based vector plasmids expressing the green fluorescent protein (GFP) under the control of the CMV promoter, the alpha-1 antitrypsin gene promoter or promoters derived from the hepatitis B virus (HBV) genome were used to compare expression in transfected and transduced cell lines. RESULTS: Hepatocyte cell lines differed strikingly in their transfectability. Transduction with replication-deficient HIV-1-based vector particles incorporating the different promoter elements was uniformly effective in hepatocyte and non-hepatocyte lines. However, in hepatocytes, only the CMV, alpha-1 antitrypsin and HBV core but not HBV surface promoters were able to produce GFP expression. Addition of the HBV enhancer 2 element improved the transducing ability of the HBV surface promoter and suppressed expression in non-hepatocytes increasing specificity for hepatocytes. CONCLUSIONS: Integrated lentiviral vectors can be used to direct transgene expression in liver cells both promiscuously and specifically. Promoters derived from the alpha-1 antitrypsin gene or HBV are alternatives to the CMV promoter. Inclusion of the HBV enhancer 2 permits strong liver-specific gene expression in vitro.

Liver transplantation.

Liver transplantation has evolved from an experimental procedure to an acceptable therapy for end-stage liver disease. The major challenges now faced are donor organ shortage, long-term complications related to immunosuppressive therapy, and the prevention and treatment of disease recurrence.