Treatment with interferons (including pegylated interferons) in patients with hepatitis B

Studies of 4 to 6 months of treatment with interferon for hepatitis B e antigen (HBeAg)-positive chronic hepatitis B virus (HBV) infection have shown clearance of HBeAg to be higher in treated patients than it is in controls by approximately 25%. These results are considerably better than those with antiviral agents. Therefore, the recent European Association for the Study of the Liver (EASL) Consensus Committee recommended the use of interferon alpha for this condition. Treatment with pegylated interferons in several trials has shown better results still. Lamivudine in combination with interferon, however, did not improve the results at 6 months after the end of therapy. In HBeAg-negative chronic HBV infection, pegylated interferon alpha is superior to lamivudine, and, again, combination with lamivudine does not improve the results. Side effects in all studies have been tolerable. Thus, these observations in chronic HBV infection, whether HBeAg-positive or HBeAg-negative, suggest an important, even primary, role for pegylated interferon therapy.

Cost-effectiveness of combination peginterferon alpha-2a and ribavirin compared with interferon alpha-2b and ribavirin in patients with chronic hepatitis C

BACKGROUND: Sustained virological response (SVR) is the primary objective in the treatment of chronic hepatitis C (CHC). Results from a recent clinical trial of patients with previously untreated CHC demonstrate that the combination of peginterferon alpha-2a and ribavirin produces a greater SVR than interferon alpha-2b and ribavirin combination therapy. However, the cost-effectiveness of peginterferon alpha-2a plus ribavirin in the U.S. setting has not been investigated. METHODS: A Markov model was developed to investigate cost-effectiveness in patients with CHC using genotype to guide treatment duration. SVR and disease progression parameters were derived from the clinical trials and epidemiologic studies. The impact of treatment on life expectancy and costs were projected for a lifetime. Patients who had an SVR were assumed to remain virus-free for the rest of their lives. In genotype 1 patients, the SVRs were 46% for peginterferon alpha-2a plus ribavirin and 36% for interferon alpha-2b plus ribavirin. In genotype 2/3 patients, the SVRs were 76% for peginterferon alpha-2a plus ribavirin and 61% for interferon alpha-2b plus ribavirin. Quality of life and costs were based on estimates from the literature. All costs were based on published U.S. medical care costs and were adjusted to 2003 U.S. dollars. Costs and benefits beyond the first year were discounted at 3%. RESULTS: In genotype 1, peginterferon alpha-2a plus ribavirin increases quality-adjusted life expectancy (QALY) by 0.70 yr compared to interferon alpha-2b plus ribavirin, producing a cost-effectiveness ratio of $2,600 per QALY gained. In genotype 2/3 patients, peginterferon alpha-2a plus ribavirin increases QALY by 1.05 yr in comparison to interferon alpha-2b plus ribavirin. Peginterferon alpha-2a combination therapy in patients with HCV genotype 2 or 3 is dominant (more effective and cost saving) compared to interferon alpha-2b plus ribavirin. Results weighted by genotype prevalence (75% genotype 1; 25% genotype 2 or 3) also show that peginterferon alpha-2a plus ribavirin is dominant. Peginterferon alpha-2a and ribavirin remained cost-effective (below $16,500 per QALY gained) under sensitivity analyses on key clinical and cost parameters. CONCLUSION: Peginterferon alpha-2a in combination with ribavirin with duration of therapy based on genotype, is cost-effective compared with conventional interferon alpha-2b in combination with ribavirin when given to treatment-naive adults with CHC.

Fibrosis correlates with a ductular reaction in hepatitis C: Roles of impaired replication, progenitor cells and steatosis

The mechanisms for progressive fibrosis and exacerbation by steatosis in patients with chronic hepatitis C (HCV) are still unknown. We hypothesized that proliferative blockade in HCV-infected and steatotic hepatocytes results in the default activation of hepatic progenitor cells (HPC), capable of differentiating into both biliary and hepatocyte lineages, and that the resultant ductular reaction promotes portal fibrosis. To study this concept, 115 liver biopsy specimens from subjects with HCV were scored for steatosis, inflammation, and fibrosis. Biliary epithelium and HPC were decorated by cytokeratin 7 immunoperoxidase, and the replicative state of hepatocytes was assessed by p21 and Ki-67 immunohistochemistry. A ductular reaction at the portal interface was common. There was a highly significant correlation between the area of ductular reaction and fibrosis stage (r = 0.453, P < .0001), which remained independently associated after multivariate analysis. HPC numbers also correlated with fibrosis (r = 0.544, P < .0001) and the ductular area (r = 0.624, P < .0001). Moreover, steatosis correlated with greater HPC proliferation (r = 0.372, P = .0004) and ductular reaction (r = 0.374, P < .0001) but was not an obligate feature. Impaired hepatocyte replication by p21 expression was independently associated with HPC expansion (P = .002) and increased with the body mass index (P < .001) and lobular inflammation (P = .005). In conclusion, the strong correlation between portal fibrosis and a periportal ductular reaction with HPC expansion, the exacerbation by steatosis, and the associations with impaired hepatocyte replication suggest that an altered regeneration pathway drives the ductular reaction. We believe this triggers fibrosis at the portal tract interface. This may be a stereotyped response of importance in other chronic liver diseases.

Re-treatment of chronic hepatitis C patients after relapse: efficacy of peginterferon-alpha-2a (40 kDa) and ribavirin

SUMMARY. We conducted a randomized multinational study to determine whether 48 weeks of re-treatment with peginterferon- alpha-2a (40 kDa) plus ribavirin would induce a sustained virological response (SVR) in relapsed chronic hepatitis C patients. Patients who had previously relapsed during 24 weeks of untreated follow-up, after having achieved an end-of-treatment virological response with 24 weeks of peginterferon-alpha-2a (40 kDa)/ribavirin combination therapy, within a phase III trial, were studied. Although the recommended dosage was the same as that used at the end of the initial trial, adjustments were permitted. Data on serious adverse events, or adverse events that resulted in dose reductions or discontinuations, were collected. Following re-treatment, the overall SVR rate in the 64 patients was 55%. The SVR rates in patients infected with hepatitis C virus (HCV) genotype 1 and non-1 genotypes were 51% and 63%, respectively. Early (week 12) virological responses were seen in 39 patients (61%) and were predictive of an SVR. Re-treatment was well tolerated. The most frequent adverse events recorded were fatigue (5%) and abdominal pain (3%). Dosages of peginterferon-alpha-2a (40 kDa) and/or ribavirin were modified because of adverse events in 3% and 13% of patients, and because of laboratory abnormalities in 23% and 5% of patients, respectively. Thus, a 48-week course of peginterferon-alpha-2a (40 kDa) plus ribavirin induces an SVR in 55% of patients who relapsed during follow-up after 24 weeks of combination therapy. Physicians should not hesitate to offer re-treatment to patients who relapse after an initial, 24-week course of combination therapy, or who have prematurely stopped treatment because, for example, of laboratory abnormalities.

Non-response to antiviral therapy is associated with obesity and increased hepatic expression of suppressor of cytokine signalling 3 (SOCS-3) in patients with chronic hepatitis C, viral genotype 1

Background: Interferon alpha (IFN-alpha) activated cellular signalling is negatively regulated by inhibitory factors, including the suppressor of cytokine signalling (SOCS) family. The effects of host factors such as obesity on hepatic expression of these inhibitory factors in subjects with chronic hepatitis C virus (HCV) are unknown. Objectives: To assess the independent effects of obesity, insulin resistance, and steatosis on response to IFN-alpha therapy and to determine hepatic expression of factors inhibiting IFN-alpha signalling in obese and nonobese subjects with chronic HCV. Methods: A total of 145 subjects were analysed to determine host factors associated with non-response to antiviral therapy. Treatment comprised IFN-alpha or peginterferon alpha, either alone or in combination with ribavirin. In a separate cohort of 73 patients, real time-polymerase chain reaction was performed to analyse hepatic mRNA expression. Immunohistochemistry for SOCS-3 was performed on liver biopsy samples from 38 patients with viral genotype 1 who had received antiviral treatment. Results: Non-response (NR) to treatment occurred in 55% of patients with HCV genotypes 1 or 4 and 22% with genotypes 2 or 3. Factors independently associated with NR were viral genotype 1/4 (p < 0.001), cirrhosis on pretreatment biopsy (p = 0.025), and body mass index >= 30 kg/m(2) (p = 0.010). Obese subjects with viral genotype 1 had increased hepatic mRNA expression of phosphoenolpyruvate carboxy kinase (p = 0.01) and SOCS-3 (p = 0.047), in comparison with lean subjects. Following multivariate analysis, SOCS-3 mRNA expression remained independently associated with obesity (p = 0.023). SOCS-3 immunoreactivity was significantly increased in obesity (p = 0.013) and in non-responders compared with responders (p = 0.014). Conclusions: In patients with chronic HCV viral genotype 1, increased expression of factors that inhibit interferon signalling may be one mechanism by which obesity reduces the biological response to IFN-alpha.

Symptom prevalence and clustering of symptoms in people living with chronic hepatitis C infection

Quality of life has been shown to be poor among people living with chronic hepatitis C However, it is not clear how this relates to the presence of symptoms and their severity. The aim of this study was to describe the typology of a broad array of symptoms that were attributed to hepatitis C virus (HCV) infection. Phase I used qualitative methods to identify symptoms. In Phase 2, 188 treatment-naive people living with HCV participated in a quantitative survey. The most prevalent symptom was physical tiredness (86%) followed by irritability (75%), depression (70%), mental tiredness (70%), and abdominal pain (68%). Temporal clustering of symptoms was reported in 62% of participants. Principal components analysis identified four symptom clusters: neuropsychiatric (mental tiredness, poor concentration, forgetfulness, depression, irritability, physical tiredness, and sleep problems); gastrointestinal (day sweats, nausea, food intolerance, night sweats, abdominal pain, poor appetite, and diarrhea); algesic (joint pain, muscle pain, and general body pain); and dysesthetic (noise sensitivity, light sensitivity, skin. problems, and headaches). These data demonstrate that symptoms are prevalent in treatment-naive people with HCV and support the hypothesis that symptom clustering occurs.

Wolbachia infections and the expression of cytoplasmic incompatibility in Drosophila sechellia and D. mauritiana

Various stocks of Drosophila mauritiana and D. sechellia were found to be infected with Wolbachia, a Rickettsia-like bacterium that is known to cause cytoplasmic incompatibility and other reproductive abnormalities in arthropods. Testing for the expression of cytoplasmic incompatibility in these two species showed partial incompatibility in D. sechellia but no expression of incompatibility in D. mauritiana. To determine whether absence of cytoplasmic incompatibility in D. mauritiana was due to either the bacterial or host genome, we transferred bacteria from D. mauritiana into an uninfected strain of D. simulans, a host species known to express high levels of incompatibility with endogenous Wolbachia. We also performed the reciprocal transfer of the natural D. simulans Riverside infection into a tetracycline-treated stock of D. mauritiana. In each case, the ability to express incompatibility was unaltered by the different host genetic background. These experiments indicate that in D. simulans and D. mauritiana expression of the cytoplasmic incompatibility phenotype is determined by the bacterial strain and that D. mauritiana harbors a neutral strain of Wolbachia.

The structure of quantum Lie algebras for the classical series, B-l, C-l and D-l

The structure constants of quantum Lie algebras depend on a quantum deformation parameter q and they reduce to the classical structure constants of a Lie algebra at q = 1. We explain the relationship between the structure constants of quantum Lie algebras and quantum Clebsch-Gordan coefficients for adjoint x adjoint --> adjoint We present a practical method for the determination of these quantum Clebsch-Gordan coefficients and are thus able to give explicit expressions for the structure constants of the quantum Lie algebras associated to the classical Lie algebras B-l, C-l and D-l. In the quantum case the structure constants of the Cartan subalgebra are non-zero and we observe that they are determined in terms of the simple quantum roots. We introduce an invariant Killing form on the quantum Lie algebras and find that it takes values which are simple q-deformations of the classical ones.

A comparison of lipopolysaccharide-induced hepatitis in ethanol-fed Wistar and Lewis rats

Elevated concentrations of plasma proinflammatory cytokines have been detected in patients with alcoholic hepatitis (AH) and in a model of lipopolysaccharide-induced hepatitis in ethanol-fed Wistar rats. These cytokines have been implicated in the pathogenesis of the liver damage. Considering the likely involvement of the immune system in AH, and the frequent use of Lewis rats in autoimmune disease models, Lewis rats were examined in the model to determine whether they would more closely mimic the immune status of a chronic alcoholic and be a preferable strain for use in future experiments. Lipopolysaccharide-induced hepatic tumor necrosis factor-cu, interleukin-1 alpha, interleukin-1 beta, and interleukin-6 mRNA expression was examined in both rat strains. The overall pattern of histological (panlobular piecemeal necrosis) and biochemical liver damage (plasma ALT levels), and cytokine expression was similar in both strains. Thus, it would appear that, despite the known susceptibility of Lewis rats to autoimmune phenomena, they do not respond to the experimental regime significantly better than Wistar rats. This study confirms that unknown mediators are contributing to the liver damage seen in this model and possibly in AH.

Chemokine and cell adhesion molecule mRNA expression and neutrophil infiltration in lipopolysaccharide-induced hepatitis in ethanol-fed rats

Neutrophil infiltration is a feature of alcoholic hepatitis (AH), and although the mechanism by which this occurs is unclear, it may involve a chemotactic gradient. We used lipopolysaccharide (LPS) to induce, in ethanol-fed rats, liver damage similar to that seen in AH. To our knowledge, this study is the first to examine the effect of ethanol on LPS-stimulated chemokine mRNA expression in this model. Hepatic cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-2, monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1 beta, MIP-2, and eotaxin mRNA levels were elevated 1 to 3 hr post-LPS in both groups. Maximal expression of MIP-2 and MCP-1 mRNA was higher in ethanol-fed rats 1 hr post-LPS, whereas CINC-2 mRNA expression was elevated above controls at 12 to 24 hr. Hepatic intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 mRNA levels were elevated in both groups at 1 hr, whereas L-selectin expression in ethanol-fed rats was elevated above controls at 12 to 24 hr. Hepatic neutrophil infiltration was highest during maximal hepatocyte necrosis. These data suggest that cell adhesion molecules, in conjunction with elevated cytokines and the subsequently induced chemokines, may assist in the formation of a chemotactic gradient within the liver, causing the neutrophil infiltration seen both in this model and possibly in AH.

Structure-activity studies of conantokins as human N-methyl-D-aspartate receptor modulators

The activities of conantokin-G (con-G), conantokin-T (con-T), and several novel analogues have been studied using polyamine enhancement of [H-3]MK-801 binding to human glutamate-N-methyl-D-aspartate (NMDA) receptors, and their structures have been examined using CD and H-1 NMR spectroscopy. The potencies of con-G[A7], con-G, and con-T as noncompetitive inhibitors of spermine-enhanced [H-3]MK-801 binding to NMDA receptor obtained from human brain tissue are similar to those obtained using rat brain tissue. The secondary structure and activity of con-G are found to be highly sensitive to amino acid substitution and modification. NMR chemical shift data indicate that con-G, con-G[D8,D17], and con-G[A7] have similar conformations in the presence of Ca2+. This consists of a helix for residues 2-16, which is kinked in the vicinity of Gla10. This is confirmed by 3D structure calculations on con-G[A7]. Restraining this helix in a linear form (i.e., con-G[A7,E10-K13]) results in a minor reduction in potency. Incorporation of a 7-10 salt-bridge replacement (con-G[K7-E10]) prevents helix formation in aqueous solution and produces a peptide with low potency. Peptides with the Leu5-Tyr5 substitution also have low potencies (con-G[Y5,A7] and con-G[Y5,K7]) indicating that Leu5 in con-G is important for full antagonist behavior. We have also shown that the Gla-Ala7 substitution increases potency, whereas the Gla-Lys7 substitution has no effect. Con-G and con-G[K7] both exhibit selectivity between NMDA subtypes from mid-frontal and superior temporal gyri, but not between sensorimotor and mid-frontal gyri. Asn8 and/or Asn17 appear to be important for the ability of con-G to function as an inhibitor of polyamine-stimulated [3H]MK-801 binding, but not in maintaining secondary structure. The presence of Ca2+ does not increase the potencies of con-G and con-T for NMDA receptors but does stabilize the helical structures of con-G, con-G[D8,D17], and, to a lesser extent, con-G[A7]. The NMR data support the existence of at least two independent Ca2+-chelating sites in con-G, one involving Gla7 and possibly Gla3 and the other likely to involve Gla10 and/or Gla14.