Acceptability of psychotherapy, pharmacotherapy, and self-directed therapies in Australians living with chronic hepatitis C.

Despite the prevalence of psychiatric co-morbidity in chronic hepatitis C (CHC), treatment is under-researched. Patient preferences are likely to affect treatment uptake, adherence, and success. Thus, the acceptability of psychological supports was explored. A postal survey of Australian CHC outpatients of the Royal Adelaide Hospital and online survey of Australians living with CHC was conducted, assessing demographic and disease-related variables, psychosocial characteristics, past experience with psychological support, and psychological support acceptability. The final sample of 156 patients (58 % male) had significantly worse depression, anxiety, stress, and social support than norms. The most acceptable support type was individual psychotherapy (83 %), followed by bibliotherapy (61 %), pharmacotherapy (56 %), online therapy (45 %), and group psychotherapy (37 %). The most prominent predictor of support acceptability was satisfaction with past use. While individual psychotherapy acceptability was encouragingly high, potentially less costly modalities including group psychotherapy or online therapy may be hampered by low acceptability, the reasons for which need to be further explored.

Safety of peginterferon alfa-2a plus ribavirin in a large multinational cohort of chronic hepatitis C patients.

BACKGROUND & AIMS: Peginterferon plus ribavirin has been the standard of care for chronic hepatitis C for a decade and an essential component of combination regimens for this disease. This large multinational open-label study aimed to better define the incidence of serious adverse events (SAEs) and non-serious adverse events of special interest in patients receiving peginterferon alfa-2a/ribavirin. METHODS: Patients were assigned at the investigator's discretion to 24- or 48-week treatment with peginterferon alfa-2a 180 µg/week and ribavirin 800 mg/day or 1000/1200 mg/day. All AEs, defined as SAEs and non-SAEs of special interest, were recorded during treatment and for 12 weeks thereafter. Non-SAEs of special interest included those leading to dose reduction/discontinuation, neutropenia, thrombocytopenia, anaemia, ALT elevations leading to dose modification and unknown/unexpected AEs. RESULTS: Of 1675 and 7178 patients assigned to 24 and 48 weeks of treatment, respectively, 87.6 and 68.3% completed therapy, whereas 6.4 and 10.3% prematurely stopped peginterferon alfa-2a treatment because of AEs. Among patients assigned to 24 and 48 weeks, 37.4 and 46.9%, respectively, reported any AE (SAE or non-SAE of special interest); 4.2 and 6.6% reported SAEs and 35.2 and 44.0% reported non-SAEs of special interest. Female gender, increasing age and cirrhosis were significantly associated with dose reductions of either drug. Increasing age (and female gender in the case of ribavirin) was significantly associated with treatment discontinuation. CONCLUSION: This study confirmed the safety and tolerability profile of peginterferon alfa-2a/ribavirin and identified patient subgroups at higher risk of dose reductions and discontinuations, thus allowing optimum management of AEs.

Differential expression of the CXCR3 ligands in chronic hepatitis C virus (HCV) infection and their modulation by HCV in vitro.

To investigate chemokine expression networks in chronic hepatitis C virus (HCV) infection, we used microarray analysis to determine chemokine expression in human infection and in chimpanzees experimentally infected with HCV. The CXCR3 chemokine family was highly expressed in both human and chimpanzee infection. CXCL10 was the only CXCR3 chemokine elevated in the serum, suggesting that it may neutralize any CXCR3 chemokine gradient established between the periphery and liver by CXCL11 and CXCL9. Thus, CXCR3 chemokines may not be responsible for recruitment of T lymphocytes but may play a role in positioning these cells within the liver. The importance of the CXCR3 chemokines, in particular CXCL11, was highlighted by replicating HCV (JFH-1) to selectively upregulate its expression in response to gamma interferon (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha). This selective upregulation was confirmed at the transcriptional level by using the CXCL11 promoter driving the luciferase reporter gene. This synergistic increase in expression was not a result of HCV protein expression but the nonspecific innate response to double-stranded RNA (dsRNA), as both in vitro-transcribed HCV RNA and the dsRNA analogue poly(I:C) increased CXCL11 expression and promoter activity. Furthermore, we show that CXCL11 is an IRF3 (interferon regulatory factor 3) response gene whose expression is selectively enhanced by IFN-gamma and TNF-alpha. In conclusion, the CXCR3 chemokines are the most significantly expressed chemokines in chronic hepatitis C and most likely play a role in positioning T cells in the liver. Furthermore, HCV can selectively increase CXCL11 expression in response to IFN-gamma and TNF-alpha stimulation that may play a role in the pathogenesis of HCV-related liver disease.

Poor outcome after liver transplantation for transthyretin amyloid neuropathy in a family with an Ala36Pro transthyretin mutation: case report.

Transthyretin amyloid polyneuropathy, caused by mutations in the transthyretin gene, is a progressive condition for which liver transplantation is an established treatment. Favorable outcomes have been described in patients with the most common transthyretin mutation, Val30Met, but outcomes have been variable in patients with other mutations. We describe the cases of 2 siblings with transthyretin amyloid polyneuropathy secondary to an infrequently reported transthyretin mutation (Ala36Pro) who underwent liver transplantation with poor outcomes.

High prevalence of late relapse and reinfection in prisoners treated for chronic hepatitis C.

BACKGROUND AND AIM: Prisoners have a high prevalence of injection drug use (IDU) and chronic hepatitis C (CHC) infection. Treatment of CHC in these patients is effective; however, their long-term outcomes following treatment are unknown. We determined the durability of a sustained virological response (SVR) in prisoners treated for CHC. METHODS: Patients were treated as part of routine clinical practice with interferon (IFN) and ribavirin. A retrospective review of medical records and a computerized pathology system was performed for clinical and laboratory information. RESULTS: Seventy-four prisoners (70 males, mean age 34 years, IDU in 55%) were evaluable for a SVR over a 12-year period to December 2008; the mean follow-up period was 1243 days. Genotype 1, 2, 3, and 6 infection was present in 18, three, 38 and three patients, respectively; the genotype was unknown in 12. Three out of 52 biopsied had cirrhosis. Standard IFN was administered to 25 (34%; 11 with ribavirin), and 49 received pegylated IFN and ribavirin; one did not complete treatment, and two had breakthrough relapses. The end-of-treatment response was achieved in 57 and SVR in 53; 14 were non-responders. Five male patients, four with unknown genotypes and treated with standard IFN alone, relapsed late (following SVR, 9%). Five patients, all treated with pegylated IFN and ribavirin, were reinfected (one prior to and four following SVR). CONCLUSIONS: Prisoners are often successfully treated for CHC. However, this retrospective study indicates that there is a high (17%) prevalence of late recurrence of viremia that is likely a reflection of reinfection due to ongoing risk-taking behavior.

Donor mannose-binding lectin deficiency increases the likelihood of clinically significant infection after liver transplantation.

BACKGROUND: Mannose-binding lectin (MBL) is an important mediator of innate immunity and is synthesized primarily by the liver. Low MBL levels are common, are due primarily to polymorphisms in the gene encoding MBL (MBL2), and are associated with an increased risk of infection, particularly when immunity is compromised. We report a large, retrospective study that examined the association between MBL status and clinically significant infection following orthotopic liver transplantation. METHODS: One hundred two donor-recipient orthotopic liver transplantation pairs were studied. Five polymorphisms in the promoter and coding regions of MBL2 were examined. MBL levels were measured, using the mannan-binding and C4-deposition assays, in serum samples obtained before and after transplantation. Associations between MBL status, as assessed by serum MBL levels and MBL2 genotype, and time to first clinically significant infection (CSI) after transplantation were examined in survival analysis with consideration of competing risks. RESULTS: The median duration of follow-up after orthotopic liver transplantation was 4 years. Thirty-six percent of recipients developed CSI after transplantation. The presence of MBL2 coding mutations in the donor was significantly associated with CSI in the recipient; the cumulative incidence function of infection was 55% in recipients of deficient livers, compared with 32% for recipients of wild-type livers (P = .002). Infection was not associated with recipient MBL2 genotype. Low MBL levels after orthotopic liver transplantation levels (mannan-binding <1 microg/mL or C4 deposition <0.2 C4 U/microL) were also associated with CSI (cumulative incidence function, 52% vs. 20%, P = .003; and cumulative incidence function, 54% vs. 24%, P = .007, respectively). In multivariate analysis, mutation in the MBL2 coding region of the donor (hazard ratio, 2.8; P = .005) and the use of cytomegalovirus prophylaxis (hazard ratio, 2.6; P = .005) were independently associated with CSI. CONCLUSIONS: Recipients of MBL-deficient livers have almost a 3-fold greater likelihood of developing CSI and may benefit from MBL replacement.

Nutritional care in hospitalized patients with chronic liver disease.

AIM: To evaluate the practice of nutritional assessment and management of hospitalised patients with cirrhosis and the impact of malnutrition on their clinical outcome. METHODS: This was a retrospective cohort study on patients with liver cirrhosis consecutively admitted to the Department of Gastroenterology and Hepatology at the Royal Adelaide Hospital over 24 mo. Details were gathered related to the patients' demographics, disease severity, nutritional status and assessment, biochemistry and clinical outcomes. Nutritional status was assessed by a dietician and determined by subjective global assessment. Estimated energy and protein requirements were calculated by Simple Ratio Method. Intake was estimated from dietary history and/or food charts, and represented as a percentage of estimated daily requirements. Median duration of follow up was 14.9 (0-41.4) mo. RESULTS: Of the 231 cirrhotic patients (167 male, age: 56.3 ± 0.9 years, 9% Child-Pugh A, 42% Child-Pugh B and 49% Child-Pugh C), 131 (57%) had formal nutritional assessment during their admission and 74 (56%) were judged to have malnutrition. In-hospital caloric (15.6 ± 1.2 kcal/kg vs 23.7 ± 2.3 kcal/kg, P = 0.0003) and protein intake (0.65 ± 0.06 g/kg vs 1.01 ± 0.07 g/kg, P = 0.0003) was significantly reduced in patients with malnutrition. Of the malnourished cohort, 12 (16%) received enteral nutrition during hospitalisation and only 6 (8%) received ongoing dietetic review and assessment following discharge from hospital. The overall mortality was 51%, and was higher in patients with malnutrition compared to those without (HR = 5.29, 95%CI: 2.31-12.1; P < 0.001). CONCLUSION: Malnutrition is common in hospitalised patients with cirrhosis and is associated with higher mortality. Formal nutritional assessment, however, is inadequate. This highlights the need for meticulous nutritional evaluation and management in these patients.

Analysis of ISG expression in chronic hepatitis C identifies viperin as a potential antiviral effector.

Interferon (IFN) alpha inhibits hepatitis C virus (HCV) replication both clinically and in vitro; however, the complete spectrum of interferon-stimulated genes (ISGs) expressed in the HCV-infected liver or the genes responsible for control of HCV replication have not been defined. To better define ISG expression in the chronically infected HCV liver, DNA microarray analysis was performed on 9 individuals with chronic hepatitis C (CHC). A total of 232 messenger RNAs were differentially regulated in CHC compared with nondiseased liver controls. A significant proportion of these were potential ISGs that were transcriptionally elevated, suggesting an ongoing response to endogenous IFN and/or double-stranded RNA. One ISG significantly elevated in all patients was viperin, an evolutionary conserved ISG that has antiviral activity against human cytomegalovirus. Stimulation of Huh-7 and HepG2 cells with IFN-alpha or -gamma revealed viperin is predominantly a type I ISG. Furthermore, viperin expression could also be induced following transfection of Huh-7 cells with either poly(I:C) or HCV RNA. Transient expression of viperin in cells harboring the HCV genomic replicon resulted in a significant decrease in HCV replication, suggesting that viperin has anti-HCV activity. In conclusion, even in the face of a persistent HCV infection, there is an active ISG antiviral cellular response, highlighting the complexity of the host viral relationship. Furthermore, ISG viperin has anti-HCV activity in vitro; we postulate that viperin, along with other ISGs, acts to limit HCV replication.

Autosomal dominant iron overload due to a novel mutation of ferroportin1 associated with parenchymal iron loading and cirrhosis.

We report the identification of a novel mutation in ferroportin1 in an Australian family with autosomal dominant iron overload. The phenotype of iron overload in one member of this family is associated with high serum ferritin concentration and elevated transferrin saturation. The pattern of iron overload in the liver shows accumulation predominantly in parenchymal cells with some Kupffer cell iron loading. Although some cases of type 4 haemochromatosis have been associated with the development of liver fibrosis this is the first report of a patient with fully established cirrhosis at a relatively young age (32 years). The coexistence of sarcoidosis in this patient may contribute to the more severe phenotype. This report highlights the phenotypic variability that can occur in type 4 haemochromatosis. Some patients have predominant reticuloendothelial iron loading and normal transferrin saturation whereas others have predominant parenchymal iron loading and elevated transferrin saturation. The reasons for this variability remain to be determined. Interestingly this is the third mutation to affect asparagine 144, reinforcing the important role for this amino acid in the function of ferroportin1.

Expression of the CXCR3 ligand I-TAC by hepatocytes in chronic hepatitis C and its correlation with hepatic inflammation.

The factors that regulate lymphocyte traffic in chronic hepatitis C (CHC) are not completely defined. Interferon (IFN)-inducible T cell alpha chemoattractant (I-TAC) is a relatively new member of the CXCR3 chemokine ligand family that selectively recruits activated T cells to sites of inflammation. To determine if I-TAC plays a role in CHC, we investigated I-TAC expression in hepatitis C virus (HCV)-infected liver biopsy material. I-TAC messenger RNA (mRNA) levels were significantly increased in HCV-infected liver compared with normal liver, which correlated with both portal and lobular inflammation. I-TAC expression was localized to hepatocytes throughout the liver lobule, with those in close proximity to active areas of inflammation expressing the highest concentration of I-TAC. In vitro, I-TAC mRNA and protein expression was inducible in Huh-7 cells following either IFN-alpha or -gamma stimulation and synergistically with tumor necrosis factor (TNF)-alpha. Furthermore, transfection of Huh-7 cells with either poly(I:C) or HCV RNA representing the HCV subgenomic replicon induced I-TAC mRNA expression. HCV replication was also found to modulate I-TAC expression, with stimulation of Huh-7 cells harboring either the HCV subgenomic or genomic replicon showing significantly increased synergistic effects compared with those previously seen in Huh-7 cells alone with IFN-gamma and TNF-alpha. In conclusion, these results suggest I-TAC, one of the most potent chemoattractants for activated T cells, is produced by hepatocytes in the HCV-infected liver and plays an important role in T cell recruitment and ultimately the pathogenesis of CHC.