Tricyclic antidepressant use and the risk of fibrosis progression in hepatitis C-infected persons: Results from ERCHIVES.

Recent preclinical studies have suggested an antifibrotic role for tricyclic antidepressants (TCA). Using the Electronically Retrieved Cohort of hepatitis C virus (HCV) Infected Veterans, we aimed to evaluate the impact of TCA use on fibrosis progression and development of hepatocellular carcinoma (HCC) among HCV-infected persons. Subjects were categorized according to use of TCAs, selective serotonin reuptake inhibitors (SSRI) or no antidepressants. TCAs or selective serotonin uptake inhibitors use was defined according to cumulative defined daily dose (cDDD), and categories were mutually exclusive. Subjects with HIV coinfection, hepatitis B surface antigen (HbsAg) positivity, cirrhosis or HCC at baseline were excluded. Outcomes were liver fibrosis progression measured by APRI scores and incident HCC. We utilized Cox proportional hazards regression to determine predictors of cirrhosis, defined as APRI > 2, and incident hepatocellular carcinoma (iHCC). Among 128 201 eligible HCV+ persons, 4% received TCAs, 43% received selective serotonin uptake inhibitors, and 53% received no antidepressants. Fewer TCAs users had drug abuse (34% and 43%) and alcohol abuse (32% vs 42%) compared to selective serotonin uptake inhibitor users. After adjusting for age, baseline APRI score, diabetes, hypertension, alcohol use, drug abuse and HCV RNA levels, TCAs use was associated with decreased risk of cirrhosis (hazard ratio [HR] = 0.77, 95% CI = 0.60, 0.99) and delayed time to development of cirrhosis, but not with decreased iHCC. In conclusion among a large cohort of HCV-positive Veterans, TCAs use was associated with decreased fibrosis progression and lower risk of developing cirrhosis. These data provide supportive evidence for the beneficial effects of TCAs on progression of liver fibrosis in patients with chronic HCV infection.

IFN-free therapy is associated with restoration of type I IFN response in HIV-1 patients with acute HCV infection who achieve SVR.

Interferon (IFN)-free direct-acting antiviral agents (DAAs) have revolutionized chronic hepatitis C virus (HCV) treatment; early studies suggest excellent efficacy in acute HCV. However, changes in innate immune responses during DAA therapy for acute HCV are unknown. We studied interferon-stimulated gene (ISG) expression and related cytokines/chemokines in HIV-infected patients with acute HCV receiving sofosbuvir plus ribavirin (SOF+RBV) as part of the A5327 clinical trial. ISG expression was determined from PBMCs, and circulating cytokines/chemokines were quantified from serum from study participants. The overall sustained virologic response (SVR) was 57%; all treatment failures were due to virologic relapse. Apart from NOS2a, baseline ISG/chemokine/cytokine levels were similar irrespective of treatment outcome. Downregulation of ISGs was observed at treatment week four and end of treatment (EOT), implicating HCV in establishing elevated ISGs early during HCV infection. Levels of many of these ISGs increased at post-treatment week 12 (PTW12) in relapsers only, coinciding with recurrent HCV RNA. Eleven ISGs were differentially expressed in responders vs relapsers. On-treatment viral suppression was also associated with a reduction in IP-10, CXCL11 and MIP-1ß levels. In contrast, circulating IFN-α levels were significantly higher at EOT and PTW12 in responders vs relapsers. Upregulation of peripheral ISG expression is established early in the course of HCV infection during acute HCV infection, but did not predict subsequent treatment outcome with SOF+RBV. ISGs were downregulated during therapy and increased post-therapy in relapsers. IFN-α levels were higher in responders at EOT/PTW12, suggesting that impaired type I IFN production/secretion may contribute to relapse.

The Natural History of Severe Acute Liver Injury.

OBJECTIVES: Acute liver failure (ALF) is classically defined by coagulopathy and hepatic encephalopathy (HE); however, acute liver injury (ALI), i.e., severe acute hepatocyte necrosis without HE, has not been carefully defined nor studied. Our aim is to describe the clinical course of specifically defined ALI, including the risk and clinical predictors of poor outcomes, namely progression to ALF, the need for liver transplantation (LT) and death. METHODS: 386 subjects prospectively enrolled in the Acute Liver Failure Study Group registry between 1 September 2008 through 25 October 2013, met criteria for ALI: International Normalized Ratio (INR)≥2.0 and alanine aminotransferase (ALT)≥10 × elevated (irrespective of bilirubin level) for acetaminophen (N-acetyl-p-aminophenol, APAP) ALI, or INR≥2.0, ALT≥10x elevated, and bilirubin≥3.0 mg/dl for non-APAP ALI, both groups without any discernible HE. Subjects who progressed to poor outcomes (ALF, death, LT) were compared, by univariate analysis, with those who recovered. A model to predict poor outcome was developed using the random forest (RF) procedure. RESULTS: Progression to a poor outcome occurred in 90/386 (23%), primarily in non-APAP (71/179, 40%) vs. only 14/194 (7.2%) in APAP patients comprising 52% of all cases (13 cases did not have an etiology assigned; 5 of whom had a poor outcome). Of 82 variables entered into the RF procedure: etiology, bilirubin, INR, APAP level and duration of jaundice were the most predictive of progression to ALF, LT, or death. CONCLUSIONS: A majority of ALI cases are due to APAP, 93% of whom will improve rapidly and fully recover, while non-APAP patients have a far greater risk of poor outcome and should be targeted for early referral to a liver transplant center.

Prevention of allograft HCV recurrence with peri-transplant human monoclonal antibody MBL-HCV1 combined with a single oral direct-acting antiviral: A proof-of-concept study.

Patients with active hepatitis C virus (HCV) infection at transplantation experience rapid allograft infection, increased risk of graft failure and accelerated fibrosis. MBL-HCV1, a neutralizing human monoclonal antibody (mAb) targeting the HCV envelope, was combined with a licensed oral direct-acting antiviral (DAA) to prevent HCV recurrence post-transplant in an open-label exploratory efficacy trial. Eight subjects received MBL-HCV1 beginning on the day of transplant with telaprevir initiated between days 3 and 7 post-transplantation. Following FDA approval of sofosbuvir, two subjects received MBL-HCV1 starting on the day of transplant with sofosbuvir initiated on day 3. Combination treatment was administered for 8-12 weeks or until the stopping rule for viral rebound was met. The primary endpoint was undetectable HCV RNA at day 56 with exploratory endpoints of sustained virologic response (SVR) at 12 and 24 weeks post-treatment. Both subjects receiving mAb and sofosbuvir achieved SVR24. Four of eight subjects in the mAb and telaprevir group met the primary endpoint; one subject achieved SVR24 and three subjects relapsed 2-12 weeks post-treatment. The other four subjects experienced viral breakthrough. There were no serious adverse events related to study treatment. This proof-of-concept study demonstrates that peri-transplant immunoprophylaxis combined with a single oral direct-acting antiviral in the immediate post-transplant period can prevent HCV recurrence.

HBV/HIV coinfection is associated with poorer outcomes in hospitalized patients with HBV or HIV.

We examined the impact of HBV/HIV coinfection on outcomes in hospitalized patients compared to those with HBV or HIV monoinfection. Using the 2011 US Nationwide Inpatient Sample, we identified patients who had been hospitalized with HBV or HIV monoinfection or HBV/HIV coinfection using ICD-9-CM codes. We compared liver-related admissions between the three groups. Multivariable logistic regression was performed to identify independent predictors of in-hospital mortality, length of stay and total charges. A total of 72 584 discharges with HBV monoinfection, 133 880 discharges with HIV monoinfection and 8156 discharges with HBV/HIV coinfection were included. HBV/HIV coinfection was associated with higher mortality compared to HBV monoinfection (OR 1.67, 95% CI 1.30-2.15) but not when compared to HIV monoinfection (OR 1.22, 95% CI 0.96-1.54). However, the presence of HBV along with cirrhosis or complications of portal hypertension was associated with three times greater in-hospital mortality in patients with HIV compared to those without these complications (OR 3.00, 95% CI 1.80-5.02). Length of stay and total hospitalization charges were greater in the HBV-/HIV-coinfected group compared to the HBV monoinfection group (+1.53 days, P < 0.001; $17595, P < 0.001) and the HIV monoinfection group (+0.62 days, P = 0.034; $8840, P = 0.005). In conclusion, HBV/HIV coinfection is a risk factor for in-hospital mortality, particularly in liver-related admissions, compared to HBV monoinfection. Overall healthcare utilization from HBV/HIV coinfection is also higher than for either infection alone and higher than the national average for all hospitalizations, thus emphasizing the healthcare burden from these illnesses.

Discontinuity of care for mothers with chronic hepatitis B diagnosed during pregnancy.

Assiduous measures are taken to prevent perinatal transmission of hepatitis B virus (HBV) to infants; it is unclear whether the mothers receive appropriate care for their chronic HBV. We sought to assess the quality of HBV care in hepatitis B surface antigen (HBsAg)-positive mothers following pregnancy. HBsAg-positive women (n = 243) who had sought prenatal care at Massachusetts General Hospital were retrospectively identified and charts reviewed. The primary outcome was adherence to the American Association for the Study of Liver Diseases (AASLD) and American College of Obstetricians and Gynecologists guidelines. Over one-third (37%) of women were first diagnosed with HBV infection at a prenatal visit. One-third (32%) did not undergo timely liver function test measurements. HBV DNA was never measured in 26% and was untimely in 34% of patients. One-third (34%) of the women were at high-risk for HCC based on AASLD criteria, yet only 33% of these women underwent timely imaging. Nearly half (49%) never saw a liver specialist for their HBV care. In multivariate analysis, women were 3.7 times more likely to have a timely ALT and 8.1 times more likely to have a timely HBV DNA if they were followed by a liver specialist (P = 0.001, <0.001). We demonstrate remarkably inadequate and discontinuous HBV care for chronically infected mothers following pregnancy. As HBV infection is already being identified prenatally, quality improvement measures encompassing obstetricians, primary care providers and hepatologists are needed to ensure that HBV-infected women are linked to care postpregnancy.

Admixture analysis of spontaneous hepatitis C virus clearance in individuals of African descent.

Hepatitis C virus (HCV) infects an estimated 3% of the global population with the majority of individuals (75-85%) failing to clear the virus without treatment, leading to chronic liver disease. Individuals of African descent have lower rates of clearance compared with individuals of European descent and this is not fully explained by social and environmental factors. This suggests that differences in genetic background may contribute to this difference in clinical outcome following HCV infection. Using 473 individuals and 792,721 single-nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS), we estimated local African ancestry across the genome. Using admixture mapping and logistic regression, we identified two regions of interest associated with spontaneous clearance of HCV (15q24, 20p12). A genome-wide significant variant was identified on chromosome 15 at the imputed SNP, rs55817928 (P=6.18 × 10(-8)) between the genes SCAPER and RCN. Each additional copy of the African ancestral C allele is associated with 2.4 times the odds of spontaneous clearance. Conditional analysis using this SNP in the logistic regression model explained one-third of the local ancestry association. Additionally, signals of selection in this area suggest positive selection due to some ancestral pathogen or environmental pressure in African, but not in European populations.

Lamivudine compared with newer antivirals for prophylaxis of hepatitis B core antibody positive livers: a cost-effectiveness analysis.

There is concern over the development of de novo hepatitis B in patients receiving liver transplants from hepatitis B surface antigen negative, hepatitis B core antibody positive donors. Current practice is to place such patients on indefinite lamivudine prophylaxis; however, there is a small risk of breakthrough infection and newer antivirals for hepatitis B are available. The objective of this study was to determine the cost-effectiveness of lamivudine compared with the newer agents, tenofovir and entecavir, in the prophylaxis setting using a Markov model. Three strategies were examined which consisted of either lamivudine or entecavir monoprophylaxis with tenofovir add-on therapy after breakthrough or tenofovir monoprophylaxis with emtricitabine add-on therapy after breakthrough. In the base case scenario, lamivudine was the most cost-effective option at a threshold of $100 000 per quality-adjusted life-year and this remained robust despite parameter uncertainty. Tenofovir had an incremental cost-effectiveness ratio of $3 540 194.77 while other strategies were superior to entecavir therapy. Until drug costs decrease, lamivudine remains the most cost-effective option for hepatitis B prophylaxis in the liver transplant setting.

Human monoclonal antibody MBL-HCV1 delays HCV viral rebound following liver transplantation: a randomized controlled study.

Rapid allograft infection complicates liver transplantation (LT) in patients with hepatitis C virus (HCV). Pegylated interferon-α and ribavirin therapy after LT has significant toxicity and limited efficacy. The effect of a human monoclonal antibody targeting the HCV E2 glycoprotein (MBL-HCV1) on viral clearance was examined in a randomized, double-blind, placebo-controlled pilot study in patients infected with HCV genotype 1a undergoing LT. Subjects received 11 infusions of 50 mg/kg MBL-HCV1 (n=6) or placebo (n=5) intravenously with three infusions on day of transplant, a single infusion on days 1 through 7 and one infusion on day 14 after LT. MBL-HCV1 was well-tolerated and reduced viral load for a period ranging from 7 to 28 days. Median change in viral load (log10 IU/mL) from baseline was significantly greater (p=0.02) for the antibody-treated group (range -3.07 to -3.34) compared to placebo group (range -0.331 to -1.01) on days 3 through 6 posttransplant. MBL-HCV1 treatment significantly delayed median time to viral rebound compared to placebo treatment (18.7 days vs. 2.4 days, p<0.001). As with other HCV monotherapies, antibody-treated subjects had resistance-associated variants at the time of viral rebound. A combination study of MBL-HCV1 with a direct-acting antiviral is underway.

Health-related quality of life in subjects with HCV/HIV coinfection: results from ACTG 5178 study.

Although health-related quality of life (HRQOL) is diminished in HCV/HIV, the relationship between virologic response and maintenance therapy with HRQOL in this population is unknown. ACTG 5178 was a phase 2, randomized trial, with three steps - Step 1: all subjects received pegylated interferon (PEG-IFN)/ribavirin (P/R) for 12 weeks. Step 2: subjects who failed to achieve early viral response (EVR) were randomized to PEG-IFN or observational control for an additional 72 weeks. Step 3: subjects with EVR from step 1 continued on P/R for a total of 72 weeks with 24 weeks follow-up off-therapy. HRQOL, symptom distress and depression levels were measured at multiple time points. In step 1 (n = 329), there was a significant decline in HRQOL in all dimensions. In step 3 (n = 169), the overall HRQOL and three of its eight dimensions (general health, role function and pain score) were increased, and achievement of sustained virologic response was associated with increased general health and cognitive function. In step 2 (n = 85), there was no significant change in HRQOL and no significant difference between groups (PEG-IFN vs observational control). There was a significant decline in HRQOL during the initial 12 weeks of therapy. Thereafter, the HRQOL profile differed for subjects with EVR vs without EVR. Maintenance therapy with PEG-IFN had no impact on the HRQOL.

HCV synergizes with body weight in the promotion of insulin resistance.

Hepatitis C virus (HCV) infection appears to contribute to the development of insulin resistance (IR). Among the multiple determinants of IR, body mass index (BMI) is the most important. We investigated the contribution of HCV to BMI-associated IR using a transgenic mouse model expressing HCV core protein. Eight transgenic and five nontransgenic littermate controls were evaluated. Glucose and insulin tolerance tests (ITT) were performed on two separate occasions. Multivariate linear mixed modelling was used to evaluate and compare the effect of weight on IR between HCV core transgenic and nontransgenic controls. There were no statistically significant differences in glucose or ITT (P = 0.58 and P = 0.59, respectively) between the two groups, and no difference in median weights between transgenic and control mice (P = 0.11). However, there was greater variance in the distributions of Tg when compared to nontransgenic mice for both glucose and insulin tolerance. When evaluating this closely, a differential contribution of weight to IR curves between these groups was noted (P = 0.05). Among nontransgenic mice, IR curves for mice of different weights were comparable, however, for transgenic mice, higher weights resulted in larger levels of IR curves with slower decay. In all animals, steatosis was absent or minimal. We conclude that weight has a greater effect on IR in HCV core expressing transgenic mice than littermate controls. HCV therefore synergizes with weight in the promotion of IR. Steatosis was not a prerequisite for the development of IR, implying that HCV's effects on IR may be independent of steatosis.

Acute hepatitis C infection lowers serum lipid levels.

Chronic hepatitis C infection is associated with hypolipidaemia that resolves with viral clearance. Lipid levels in a subgroup of patients rebound to levels that may increase the risk of coronary heart disease. The impact of acute hepatitis C infection and its clearance on lipid levels is unknown. We undertook a retrospective evaluation of subjects with acute hepatitis C infection evaluating lipid levels before, during and following acute infection. Thirty-eight subjects with acute hepatitis C infection had lipid levels available. Twelve patients had pre-infection and intra-infection lipid levels available. Cholesterol (197.8-152.4 mg/dL, P = 0.025), low-density lipoprotein (LDL) (116.1-76.3 mg/dL, P = 0.001) and non-high-density lipoprotein (non-HDL) cholesterol (164.0-122.7 mg/dL, P = 0.007) decreased dramatically during acute hepatitis C virus infection. Nineteen patients who achieved viral clearance had lipid levels available during infection and following resolution of infection. In these patients, cholesterol (145.0-176.0 mg/dL, P = 0.01), LDL (87.0-110.1 P = 0.0046) and non-HDL cholesterol (108.6-133.6 mg/dL, P = 0.008) increased significantly. No change was seen in patients who developed chronic infection. Four patients had lipid levels before, during and following resolution of infections and had increased postinfection LDL, cholesterol and non-HDL cholesterol from pre-infection levels, indicating acute infection may be associated with an increase in postinfection lipid levels and may confer an increased risk of coronary heart disease. Acute hepatitis C infection results in hypolipidaemia with decreased LDL, cholesterol and non-HDL cholesterol levels that increase following infection resolution. Levels may increase above pre-infection baseline lipid levels and should be monitored.

Analysis of successful immune responses in persons infected with hepatitis C virus.

Although hepatitis C virus (HCV) infection is very common, identification of patients during acute infection is rare. Consequently, little is known about the immune response during this critical stage of the disease. We analyzed the T lymphocyte response during and after acute resolving HCV infection in three persons, using interferon (IFN)-gamma enzyme-linked immunospot (ELISPOT) and human histocompatibility leukocyte antigen (HLA) peptide tetramer assays. Acute infection was associated with a broadly directed T helper and cytotoxic T lymphocyte (CTL) response, which persisted after resolution of clinical hepatitis and clearance of viremia. At the earliest time point studied, highly activated CTL populations were observed that temporarily failed to secrete IFN-gamma, a "stunned" phenotype, from which they recovered as viremia declined. In long-term HCV-seropositive persons, CTL responses were more common in persons who had cleared viremia compared with those with persistent viremia, although the frequencies of HCV-specific CTLs were lower than those found in persons during and after resolution of acute HCV infection. These studies demonstrate a strong and persistent CTL response in resolving acute HCV infection, and provide rationale to explore immune augmentation as a therapeutic intervention in chronic HCV infection.

Factors associated with rapid and early virologic response to peginterferon alfa-2a/ribavirin treatment in HCV genotype 1 patients representative of the general chronic hepatitis C population.

Rapid virologic response (RVR) and complete early virologic response (cEVR) are associated with sustained virologic response to hepatitis C virus (HCV) therapy. We retrospectively examined baseline and on-treatment factors associated with RVR (HCV RNA undetectable at week 4) and cEVR (HCV RNA undetectable at week 12, regardless of week 4 response). The analysis comprised 1550 HCV genotype-1 patients from five clinical trials, including three enriched with difficult-to-treat populations, randomized to peginterferon alfa-2a 180 microg/week plus ribavirin 1000-1200 mg/day. Overall, 15.6% achieved RVR and 54.0% achieved cEVR. Baseline factors predictive of RVR were serum HCV RNA 3 x ULN (OR: 2.01; P < 0.0001), non-cirrhotic status (OR: 1.92; P = 0.0087), age 13 mg/kg/day was predictive of RVR (OR: 1.69; P = 0.005) and cEVR (OR: 1.24; P = 0.09), whereas peginterferon alfa-2a dose reduction was not. Greater decreases in haematologic parameters were observed in patients who achieved cEVR compared with patients who did not. In conclusion, several baseline and on-treatment factors were associated with RVR and cEVR to peginterferon alfa-2a plus ribavirin in difficult-to-treat HCV genotype-1 patients, providing important prognostic information on the antiviral response in a patient cohort that is reflective of the general chronic hepatitis C population.

Early treatment improves outcomes in acute hepatitis C virus infection: a meta-analysis.

Acute hepatitis C virus infection is associated with high rates of spontaneous clearance and variable rates of treatment-induced clearance. The benefit of early treatment versus awaiting spontaneous clearance is unknown, as is the optimal timing of treatment.We performed a MEDLINE and EMBASE search for the time period 1950 to October 2008. All English language abstracts using the search terms acute hepatitis C, hepatitis C and acute and hepatitis C and acute disease or acute infection were reviewed. Bibliographies were reviewed.Twenty-two studies including 1075 patients met the inclusion criteria. The sustained virologic response (SVR) rate for treated patients was 78%, significantly higher than 55.1% in untreated patients (OR = 3.08, 95% CI: 1.8-4.8 P value <0.0001). Mean time from diagnosis to spontaneous clearance was 9.7 weeks (SD 6.5). SVR rates varied inversely with time from acute HCV diagnosis. SVR rates for treatment within 12 weeks was 82.5% (95% CI: 75.6-89.3), significantly better than the clearance rates in untreated patients (P < 0.001). Response rates fell to 66.9% for treatment between 12 and 24 weeks, and decreased further to 62.5% for treatment beyond 24 weeks. Rates of viral clearance in treated patients with acute hepatitis C virus infection were significantly higher than that in untreated patients. Treatment rates were highest when treatment was initiated within 12 weeks of diagnosis. Based on these findings, we would advocate a 12 week period of observation for spontaneous clearance before treatment initiation. If no clearance has occurred by 12 weeks, treatment should be initiated.

Proton pump inhibitors are associated with accelerated development of cirrhosis, hepatic decompensation and hepatocellular carcinoma in noncirrhotic patients with chronic hepatitis C infection: results from ERCHIVES.

BACKGROUND: Proton pump inhibitors are among the most commonly prescribed medications in the United States. Their safety in cirrhosis has recently been questioned, but their overall effect on disease progression in noncirrhotic patients with chronic liver disease remains unclear. AIM: To determine the impact of proton pump inhibitors on the progression of liver disease in noncirrhotic patients with hepatitis C virus (HCV) infection. METHODS: Using the electronically retrieved cohort of HCV-infected veterans (ERCHIVES) database, we identified all subjects who received HCV treatment and all incident cases of cirrhosis, hepatic decompensation and hepatocellular carcinoma. Proton pump inhibitor use was measured using cumulative defined daily dose. Multivariate Cox regression analysis was performed after adjusting univariate predictors of cirrhosis and various indications for proton pump inhibitor use. RESULTS: Among 11 526 eligible individuals, we found that exposure to proton pump inhibitors was independently associated with an increased risk of developing cirrhosis (hazard ratio [HR]: 1.32; 95% confidence interval: [1.17, 1.49]). This association remained robust to sensitivity analysis in which only patients who achieved sustained virologic response were analysed as well as analysis excluding those with alcohol abuse/dependence. Proton pump inhibitor exposure was also independently associated with an increased risk of hepatic decompensation (HR: 3.79 [2.58, 5.57]) and hepatocellular carcinoma (HR: 2.01 [1.50, 2.70]). CONCLUSIONS: In patients with chronic HCV infection, increasing proton pump inhibitor use is associated with a dose-dependent risk of progression of chronic liver disease to cirrhosis, as well as an increased risk of hepatic decompensation and hepatocellular carcinoma.

Interleukin 1 beta initially sensitizes and subsequently protects murine intestinal stem cells exposed to photon radiation.

Interleukin 1 (IL-1) has been shown to prevent early bone marrow-related death following total-body irradiation, by protecting hematopoietic stem cells and speeding marrow repopulation. This study assesses the effect of IL-1 on the radiation response of the intestinal mucosal stem cell, a nonhematopoietic normal cell relevant to clinical radiation therapy. As observed with bone marrow, administration of human recombinant IL-1 beta (4 micrograms/kg) to C3H/Km mice 20 h prior to total-body irradiation modestly protected duodenal crypt cells. In contrast to bone marrow, IL-1 given 4 or 8 h before radiation sensitized intestinal crypt cells. IL-1 exposure did not substantially alter the slope of the crypt cell survival curve but did affect the shoulder: the X-ray survival curve was offset to the right by 1.01 +/- 0.06 Gy when IL-1 was given 20 h earlier and by 1.28 +/- 0.08 Gy to the left at the 4-h interval. Protection was greatest when IL-1 was administered 20 h before irradiation, but minimal effects persisted as long as 7 days after a single injection. The magnitude of radioprotection at 20 h or of radiosensitization at 4 h increased rapidly as IL-1 dose increased from 0 to 4 micrograms/kg. However, doses ranging from 10 to 100 micrograms/kg produced no further difference in radiation response. Animals treated with saline or IL-1 had similar core temperatures from 4 to 24 h after administration, suggesting that thermal changes were not responsible for either sensitization or protection. Mice irradiated 20 h after IL-1 had significantly greater crypt cell survival than saline-treated irradiated controls at all assay times, which ranged from 54 to 126 h following irradiation. The intervals to maximum crypt depopulation and initiation of repopulation were identical in both saline- and IL-1-treated groups, suggesting that IL-1 altered absolute stem cell survival but not the kinetics of repopulation.

HBV infection is associated with greater mortality in hospitalised patients compared to HCV infection or alcoholic liver disease.

BACKGROUND: Little is known about outcomes of Hepatitis B virus (HBV)-related hospitalisations. AIM: To compare the characteristics and outcomes of hospitalised HBV patients to those with Hepatitis C virus (HCV) infection and alcoholic liver disease (ALD), and to examine variables associated with poor outcomes. METHODS: Using the 2011 US Nationwide Inpatient Sample, we identified hospitalised patients with HBV, HCV or ALD-related admissions using ICD-9-CM codes. We compared liver-related complications between the three groups. Multivariable regression was performed to identify factors associated with in-hospital mortality and length of stay. RESULTS: A total of 22 843 HBV, 203 300 HCV and 244 383 ALD-related discharges were included. Cirrhosis was noted less commonly in those with HBV (69.1%) compared to HCV (83.9%) or ALD (80.9%) (P < 0.001). In contrast, hepatocellular cancer and acute liver failure were more common with HBV (16.5% and 5.2%) compared to HCV (10.4% and 2.8%) or ALD (2.5% and 4.9%) respectively (P < 0.0001). On multivariable analysis, adjusting for demographics, liver and nonliver comorbidity, HBV infection was associated with higher mortality compared to HCV infection [Odds ratio (OR) 1.21, 95% CI: 1.04-1.39) or ALD (OR: 1.21, 95% CI: 1.05-1.40). Length of hospital stay was greater with HBV compared to HCV (+0.54 days) or ALD (+0.36 days). Among those with HBV, significant factors associated with mortality included renal failure, hepatocellular cancer, respiratory failure, ascites, coagulopathy and acute liver failure. CONCLUSION: Patients hospitalised with HBV infection represent a particularly high-risk group with poor in-hospital outcomes and increased mortality compared to HCV infection or alcoholic liver disease.

Idiopathic giant esophageal ulcers in a renal transplant patient responsive to steroid therapy.

Idiopathic giant esophageal ulcers in immunocompromised patients have been described only in patients with acquired immunodeficiency syndrome. A solitary report of an idiopathic giant esophageal ulcer in an immunocompetent patient exists. We describe a case of idiopathic esophageal ulceration ultimately responsive to steroid therapy in a 31-year old immunosuppressed, human immunodeficiency virus-negative renal transplant patient. The case is described with particular reference to the evaluation, differential diagnosis, and therapeutic response to steroids. Similarities in presentation and treatment to giant esophageal ulcers in human immunodeficiency virus infection suggest an underlying immune defect as the likely cause. This is the first described case of giant esophageal ulceration responsive to steroids in an immunosuppressed human immunodeficiency virus-negative patient. This entity should be added to the differential diagnosis of esophageal ulceration in solid organ transplant recipients.