Asymptomatic Hepatitis C Virus Carriers Research Articles

Cognitive Performance in Asymptomatic Elderly People with Hepatitis C: The Role of Education.

Neurotropism of the hepatitis C virus (HCV) can be the source of subtle neuropsychological symptoms in non-cirrhotic patients. Age is a risk factor for cognitive impairment (CI). Thus, asymptomatic elderly people who carry HCV might be at a greater risk of CI. Education can influence test performance. (1) To verify whether elderly people with HCV performed poorer than controls on cognitive tests. (2) To analyze how education affects performance. (3) To verify whether the extent of the effect of education on performance depends on the group (HCV vs. controls) and the type of cognitive test. Asymptomatic HCV carriers older than 60 years (n = 41) were matched with 41 corresponding controls. All participants performed the following tests: Mini-Cog, Mini Mental State Examination, clock drawing test (CDT), and verbal fluency. (1) There were no significant differences in cognitive performance between the two groups. (2) Higher education was always associated with better performance. (3) There was a significant group difference in the slopes of the regression lines between years of education and CDT performance. No differences were found for the other three tests. Considering the scores on the CDT, the rate of improvement in performance when schooling increases is higher in HCV carriers.

PIN55 Cost-Effectiveness of Hepatitis C VIRUS Screening, and Subsequent Monitoring or Treatment Among Pregnant Women in the Netherlands

The prevalence of diagnosed chronic hepatitis C virus (HCV) infection among pregnant women in the Netherlands is 0.26%, yet many cases remain undiagnosed. HCV screening and treatment of pregnant HCV carriers could reduce the burden of disease and limit vertical transmission from mother to child. This study aims to assess the impact of HCV screening and subsequent treatment with new direct-acting antivirals among pregnant women in the Netherlands. An HCV natural history Markov transition state model was developed, to evaluate the cost-effectiveness of HCV screening and treatment. Besides all 179,000 pregnant women in the Netherlands (cohort 1), we modelled three further cohorts: all 79,000 first-time pregnant women (cohort 2), 33,000 pregnant migrant women (cohort 3) and 16,000 first-time pregnant migrant women (cohort 4). Each cohort was analyzed in various scenarios: (i) no intervention, i.e. the current practice, (ii) screen-and-treat, i.e. the most extensive approach involving treatment of all individuals found HCV-positive, and (iii) screen-and-treat/monitor, i.e. a strategy involving treatment of symptomatic patients and follow-up of asymptomatic HCV carriers with subsequent treatment only at progression. For all studied cohorts, comparison between scenarios (ii) and (i) resulted in ICERs varying between €8,343 and €9,182 per QALY gained, with a budget impact varying from €11,283,830 to €34,502,880. For all cohorts, comparison between scenarios (iii) and (i) resulted in ICERs between €1,566 and €2,518 per QALY gained with budget impact varying from €1,668,670 to €6,534,650. For all cohorts, the ICERs involved in potentially unnecessary treatment of asymptomatic HCV carriers varied between €52,432 and €53,641, well above the willingness-to-pay (WTP) threshold of €20,000 per QALY gained. Screening for HCV among all pregnant women in the Netherlands is cost-effective. However, for active screening and treatment, it would be most reasonable to consider smaller risk groups in view of the budget impact.

Cost-effectiveness of hepatitis C virus screening, and subsequent monitoring or treatment among pregnant women in the Netherlands

BackgroundThe prevalence of diagnosed chronic hepatitis C virus (HCV) infection among pregnant women in the Netherlands is 0.26%, yet many cases remain undiagnosed. HCV screening and treatment of pregnant HCV carriers could reduce the burden of disease and limit vertical transmission from mother to child. We assessed the impact of HCV screening and subsequent treatment with new direct-acting antivirals (DAAs) among pregnant women in the Netherlands.MethodsAn HCV natural history Markov transition state model was developed, to evaluate the public-health and economic impact of HCV screening and treatment. Besides all 179,000 pregnant women in the Netherlands (cohort 1), we modelled 3 further cohorts: all 79,000 first-time pregnant women (cohort 2), 33,000 pregnant migrant women (cohort 3) and 16,000 first-time pregnant migrant women (cohort 4). Each cohort was analyzed in various scenarios: i no intervention, i.e., the current practice, ii screen-and-treat, i.e., the most extensive approach involving treatment of all individuals found HCV-positive, and iii screen-and-treat/monitor, i.e., a strategy involving treatment of symptomatic (F1–F4) patients and follow-up of asymptomatic (F0) HCV carriers with subsequent treatment only at progression.ResultsFor all cohorts, comparison between scenarios (ii) and (i) resulted in ICERs between €9,306 and €10,173 per QALY gained and 5 year budget impacts varying between €6,283,830 and €19,220,405. For all cohorts, comparison between scenarios (iii) and (i) resulted in ICERs between €1,739 and €2,749 per QALY gained and budget impacts varying between €1,468,670 and €5,607,556. For all cohorts, the ICERs (scenario iii versus ii) involved in delayed treatment of asymptomatic (F0) HCV carriers varied between €56,607 and €56,892, well above the willingness-to-pay (WTP) threshold of €20,000 per QALY gained and even above a threshold of €50,000 per QALY gained.ConclusionUniversal screening for HCV among all pregnant women in the Netherlands is cost-effective. However, it would be reasonable to consider smaller risk groups in view of the budget impact of the intervention.

Interaction effects among IFN-γ+874, IL-2-330, IL-10-1082, IL-10-592 and IL-4-589 polymorphisms on the clinical progression of subjects infected with hepatitis B virus and/or hepatitis C virus: a retrospective nested case–control study

BackgroundThe natural outcomes of hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections vary considerably among individuals The infection may heal naturally, or patients may succumb to chronic liver...

Radiation Dosimetry and Biodistribution in Monkey and Man of 11C-PBR28: A PET Radioligand to Image Inflammation

(11)C-PBR28 ([methyl-(11)C]N-acetyl-N-(2-methoxybenzyl)-2-phenoxy-5-pyridinamine) is a recently developed radioligand to image peripheral benzodiazepine receptors (PBRs) in brain. The aim of this study was to estimate the human radiation doses of (11)C-PBR28 based on biodistribution data in monkeys and humans. In addition, we scanned 1 human subject who fortuitously behaved as if he lacked the PBR binding protein. Whole-body PBR images were acquired after intravenous bolus administration of (11)C-PBR28 in 7 healthy humans (651 +/- 111 MBq) and 2 rhesus monkeys (370 +/- 59.9 MBq). One monkey was scanned after receptor blockade with PK 11195 (10.7 mg/kg intravenously). For typical subjects (subjects 1-6), the 3 organs with highest exposure were those with the high PBR densities (kidneys, spleen, and lungs), and the effective dose was 6.6 microSv/MBq. The unusual subject (subject 7) had 60%-90% less uptake in these 3 organs, resulting in 28% lower effective dose. The activity in the baseline monkey scans was greater than that in humans for organs with high PBR densities. For this reason, the human effective dose was overestimated by 60% with monkey biodistribution data. The monkey with receptor blockade had an overall distribution qualitatively similar to that of the unusual human subject (subject 7), with decreased exposure to lungs, kidney, and spleen. The effective dose of (11)C-PBR28 was modest and was similar to that of several other (11)C-radioligands. Lack of receptor binding in the unusual human subject and in the monkey with receptor blockade decreased exposure to organs with high PBR densities and enhanced uptake in excretory and metabolic pathways.

Clinical Significance of Evaluation of Serum Zinc Concentrations in C-Viral Chronic Liver Disease

We evaluated zinc concentrations in patients with hepatitis C virus (HCV)-positive chronic liver disease and correlated them with the clinical profiles of the patients. A total of 100 patients with chronic hepatitis (CH), 29 with liver cirrhosis (LC), and 6 who were asymptomatic HCV carriers (ASC) were examined. All of the patients were positive for serum HCV RNA. One hundred eighteen HCV antibody-positive hepatocellear carcinoma (HCC) patients and 11 healthy subjects also were included in this study. Serum zinc concentrations were evaluated using conventional atomic absorption spectrometry. The median concentration of zinc in patients with CH was statistically lower than that in healthy control subjects. The median zinc concentrations of the LC and HCC groups were significantly lower than that of the CH group. A significant correlation was observed between the zinc concentrations and the platelet counts and albumin concentrations. The zinc concentrations did not correlate with tumor size and number and decreased with the development of Child-Pugh stage. The cumulative survival rate after therapy for HCC nodules in the low zinc concentration group was significantly lower than in the high group. We conclude that the serum concentration of zinc influences the clinical profiles in patients with C-viral chronic liver disease.

Identification of a new autoantibody in patients with chronic hepatitis

To comprehensively study autoantibodies in patients with chronic hepatitis (CH), especially those with hepatitis C virus (HCV) infection, proteins extracted from HepG2 cells were separated by two-dimensional electrophoresis. Spots reacting with sera from 15 patients with CH-C were detected by Western blotting. Proteins extracted from the spots were subjected to mass spectroscopy for identification by mass fingerprinting. Antigenicity of the proteins identified was confirmed by Western blotting and enzyme-linked immunoabsorbent assay. The localization of the autoantigens so detected was investigated by immunohistochemistry. Among 20 protein spots detected, four were identified as actin, heat shock protein (HSP) 70, HSP60, and a novel protein (hepalaminin). Hepalaminin consists of two domains of laminin β-2 and a specific domain. Autoantibodies against the specific domain were detected in 60.8% of patients with CH-C, 37.7% of those with CH-B, 42.3% of those with autoimmune CH, 28.6% of nonalcoholic steatohepatitis, 10.0% of asymptomatic HCV carriers, but in no healthy volunteers. Antihepalaminin positivity in CH-C and CH-B was related to histologic grading. Immunohistochemical staining demonstrated that hepalaminin is present in the cytoplasm of hepatocytes and cholangiocytes but not of fibroblasts or the vascular epithelium. Hepalaminin is a novel protein expressed in hepatocytes and cholangiocytes. Autoimmunity to this protein may exacerbate inflammation in chronic viral hepatitis.

Production of interleukins 10 and 12 by peripheral blood mononuclear cells (PBMC) in chronic hepatitis C virus (HCV) infection.

We previously reported that interferon-gamma (IFN-gamma) production by PBMC in response to HCV core protein was increased in patients with type C chronic liver disease. To understand better the pathophysiology of this disease, we evaluated production of IL-10 and IL-12 by PBMC from 41 patients with chronic HCV infection, including asymptomatic HCV carriers with persistently normal serum ALT values. IL-10 is known to inhibit many effector functions of the immune system, suppressing Th1-type cell development, while IL-12 stimulates differentiation of Th1-type cells, facilitating cell-mediated immunity. IL-10 production was determined by culturing lymphocytes with concanavalin A (Con A), while IL-12 was produced by monocytes in the presence of Staphylococcus aureus Cowan 1 (SAC) with or without recombinant HCV core protein, respectively. The cytokine levels in culture supernatants were measured by ELISA. Spontaneous IL-10 production was greater in patients with chronic hepatitis (CH) (229 +/- 119 pg/ml, P < 0.01) and liver cirrhosis (LC) (185 +/- 88 pg/ml, P < 0.05) than in controls (119 +/- 27 pg/ml), while it was decreased during IFN treatment (70 +/- 25 pg/ml). Both HCV core protein and Con A enhanced IL-10 production by cells from HCV-infected patients. IL-12 was not detectable in medium alone cultures, and SAC-induced IL-12 production did not differ between various patient groups and controls. Simultaneous addition of HCV protein resulted in an increase of IL-12 production in chronic liver disease compared with SAC-alone cultures. Addition of IL-10 to the cultures equally suppressed IFN-gamma production for both controls and patient groups, but the enhancing effect of IL-12 on IFN-gamma production was significantly less in LC than in controls and other patient groups. The findings suggest that secretion of IL-10/IL-12 by cells from control individuals and various patient groups may be different, and that the cytokines might show different effects on IFN-gamma production by some cells.

Autoantibodies to CD69 in Patients with Chronic Hepatitis Type C: A Candidate Marker for Predicting the Response to Interferon Therapy

Objective: To understand the autoimmunity associated with chronic hepatitis C (CHC), we investigated autoantibodies (autoAbs) to CD69. Methods: With this aim, we tested the reactivity of serum samples from patients with CHC and asymptomatic carriers of hepatitis C virus (HCV), as well as from patients with chronic hepatitis B (CHB) and autoimmune hepatitis (AIH), to recombinant CD69 molecules. Results: Frequencies of anti-CD69 autoAbs were 38.7% in CHC, 15.8% in AIH and 12.3% in CHB. None of the tested asymptomatic HCV carriers had autoAbs to CD69. It is important clinically that the presence of anti-CD69 autoAbs was found to be associated with a poor response to interferon-α (IFN-α) therapy. In the epitope analysis, multiple epitopes were mapped on CD69, indicating antigen-driven production of the autoAbs. Conclusion: We evidenced existence of anti-CD69 autoAbs in patients with CHC, and found that the anti-CD69 autoAb may have potential for predicting responses to IFN-α therapy.

Production of interleukins 10 and 12 by activated peripheral blood monocytes/macrophages in patients suffering from chronic hepatitis C virus infection with respect to the response to interferon and ribavirin treatment

Circulating monocytes/macrophages are important for the initiation of immune responses to hepatitis C virus (HCV). Their presentation capacities and production of immunoregulatory cytokines enable them to activate cellular immune responses which is critical in determining the outcome of infection. We used flow cytometry to examine the expression of a CD80 costimulatory molecule on the surface of peripheral blood CD14+ monocytes/macrophages and to analyse the production of IL10 and IL12 by these cells. Forty-three individuals (6 asymptomatic HCV carriers, 37 patients with chronic hepatitis C (CHC)) were enrolled in this study. Thirty-seven patients with CHC (23 responders and 14 non-responders, NR) received combination (interferon+ribavirin) treatment for 52 weeks. The baseline percentage of CD14+CD80+ peripheral blood monocytes/macrophages was high in patients with CHC ( P<0.001) and returned to normal after the treatment. All patients with CHC showed significantly high production of IL10 ( P<0.001). In asymptomatic HCV carriers production level of this cytokine tended to be higher than in patients with CHC ( P<0.001). A baseline production of IL12 was higher in asymptomatic HCV carriers and patients with CHC compared to healthy controls ( P<0.001). The level of IL12 production was increased in treatment responders whereas in NR returned to normal value. Our data argue against functional impairment of circulating monocytes/macrophages during HCV infection. Furthermore, the positive therapeutic outcome following combination treatment might associate with increased production of IL12 by these cells.

Comparison of clinical laboratory liver tests between asymptomatic HBV and HCV carriers with persistently normal aminotransferase serum levels

We examined the clinicopathological state in asymptomatic hepatitis C virus (HCV) carriers with persistently normal aminotransferase serum levels in comparison with asymptomatic hepatitis B virus (HBV) carriers. The findings showed that the thymol turbidity test (TTT) values and zinc sulfate turbidity test (ZTT) values were significantly higher in asymptomatic HCV carriers than in asymptomatic HBV carriers, whose values were within the normal limits. Multivariate analysis showed that the independent predictor of serum TTT and ZTT levels was the HCV infection. In clinical state, simple and cheap tests such as TTT and ZTT are useful for mass screening to detect HCV carriers in medical check-ups of healthy workers.

Increased frequency of interferon-gamma-producing peripheral blood CD4+ T cells in chronic hepatitis C virus infection.

To determine the profile of cytokine secretion by CD4+ T helper (Th) cells in chronic hepatitis C virus (HCV) infection, we used flow cytometry to determine the percentage of interferon (IFN)-gamma and interleukin (IL)-4 producing cells from CD4+ T lymphocytes in peripheral blood obtained from patients chronically infected with HCV. Peripheral blood mononuclear cells isolated from 89 HCV infected subjects (22 asymptomatic carriers, 56 patients with chronic hepatitis, and 11 patients with liver cirrhosis) and 24 healthy controls were stained with surface CD4 and intracellular IFN-gamma and IL-4. Serum soluble IL-2 receptor (sIL-2R) levels were analyzed by ELISA. The frequency of IFN-gamma producing CD4+ cells in asymptomatic HCV carriers, patients with chronic hepatitis, and patients with liver cirrhosis were significantly higher than those of healthy controls (p<0.01, respectively). In contrast, the percentages of IL-4-producing CD4+ cells were very low, and there were no significant correlations with disease progression. A significant elevation in serum sIL-2R levels was found in chronic HCV infection compared to healthy controls, and serum sIL-2R levels significantly correlated with the frequency of IFN-gamma-producing cells. In HCV infected subjects, both serum sIL-2R and IFN-gamma are increased in chronic HCV infection no matter the stage of disease, meaning they are no different in asymptomatic carriers, patients with chronic hepatitis, and patients with liver cirrhosis, and that Th1 cytokine or Th1 cells may participate in the pathogenesis of liver damage in chronic HCV infection.

Increased frequency of interferon-γ-producing peripheral blood CD4 + T cells in chronic hepatitis C virus infection

OBJECTIVES: To determine the profile of cytokine secretion by CD4 + T helper (Th) cells in chronic hepatitis C virus (HCV) infection, we used flow cytometry to determine the percentage of interferon (IFN)-γ and interleukin (IL)-4 producing cells from CD4 + T lymphocytes in peripheral blood obtained from patients chronically infected with HCV. METHODS: Peripheral blood mononuclear cells isolated from 89 HCV infected subjects (22 asymptomatic carriers, 56 patients with chronic hepatitis, and 11 patients with liver cirrhosis) and 24 healthy controls were stained with surface CD4 and intracellular IFN-γ and IL-4. Serum soluble IL-2 receptor (sIL-2R) levels were analyzed by ELISA. RESULTS: The frequency of IFN-γ producing CD4 + cells in asymptomatic HCV carriers, patients with chronic hepatitis, and patients with liver cirrhosis were significantly higher than those of healthy controls ( p < 0.01, respectively). In contrast, the percentages of IL-4-producing CD4 + cells were very low, and there were no significant correlations with disease progression. A significant elevation in serum sIL-2R levels was found in chronic HCV infection compared to healthy controls, and serum sIL-2R levels significantly correlated with the frequency of IFN-γ-producing cells. CONCLUSIONS: In HCV infected subjects, both serum sIL-2R and IFN-γ are increased in chronic HCV infection no matter the stage of disease, meaning they are no different in asymptomatic carriers, patients with chronic hepatitis, and patients with liver cirrhosis, and that Th1 cytokine or Th1 cells may participate in the pathogenesis of liver damage in chronic HCV infection.

Hepatitis C virus RNA profiles in chronically infected individuals: do they relate to disease activity?

Fluctuations of hepatitis C virus (HCV)-RNA serum levels were monitored in a multicenter study in 76 chronic HCV carriers who had been followed longitudinally without receiving antiviral therapy to assess their relation with the course of liver disease activity. Forty-four patients had normal transaminases over more than 2 years, while 32 additional patients had fluctuating levels. Viral load was measured in serial serum samples prospectively collected for 10 to 12 months in 54 patients and in sera stored yearly up to 8 years in an additional 22 patients. In patients tested monthly, a lesser extent of fluctuations was detected in cases with constantly normal transaminases as compared with those with fluctuating transaminases. In the former group, the mean difference between maximum and minimum values observed in each individual patient was 0.7 Log, while in the latter group, it was 1.3 Log (P =.0004). Most of these patients experienced, on average, three peaks of viremia over 1 year. The range of variation observed upon yearly testing was between 0.2 and 2.2 Log and did not reach statistical significance between the two groups. In conclusion, a careful viral replication profile can be achieved only by monthly testing, because longer time intervals could miss viremia fluctuations. HCV-RNA levels are more stable in asymptomatic HCV carriers than in patients with biochemical activity of liver disease.

Hepatitis C virus-related liver damage is related to cold activation of complement.

A high positivity of cold activation of complement has been reported in Japanese patients having hepatitis B virus-negative chronic hepatitis. Although the cause of cold activation of complement is unknown, the involvement of hepatitis C virus (HCV) has been suspected. We studied the positivity of cold activation of complement in 253 patients, including 93 patients with chronic hepatitis C infection who received 6MU natural interferon-alpha per day for 24 continuous weeks. Cold activation was positive in 38% of patients with chronic hepatitis C and in 46% of patients with liver cirrhosis C. We did not detect cold activation in asymptomatic HCV carriers; patients with chronic hepatitis B, liver cirrhosis B, or alcohol-related liver damage; or in the controls. Cold activation was also negative in HCV-RNA-negative patients who responded completely to interferon-alpha, and in HCV-RNA-positive patients who responded partially whose serum alanine transaminase levels were normalized after interferon treatment. In the patients who had a relapse of hepatitis C after interferon treatment, positivity of cold activation increased sharply. We conclude that HCV-associated liver damage is related to the development of cold activation of complement. Cold activation is useful for monitoring the response to interferon in patients with chronic hepatitis C infection.

Association of production of interleukin-1 β in chronic hepatitis C virus infection with presence of hepatitis C virus RNA in peripheral blood mononuclear cells

Hepatic fibrosis is associated with excessive in vitro lipopolysaccharide (LPS)-induced production of interleukin- 1 (IL-1) in chronic liver diseases (chronic hepatitis B, primary biliary cirrhosis, and alcoholic cirrhosis etc). We measured IL-1 β production in LPS-stimulated peripheral blood mononuclear cells (PBMC) from patients with chronic hepatitis C virus (HCV) infection. The levels of IL-1 β production in chronic HCV infection were significantly higher than in healthy controls, but were not correlated with the grade of hepatic fibrosis, the levels of hepatic inflammation, or the levels of HCV RNA in serum. Asymptomatic HCV carriers showed equivalent levels of IL-1 β production to patients with chronic active hepatitis and liver cirrhosis (10.59±4.76, 11.52±2.03 and 11.18±4.05 ng/ml, respectively). The levels of IL-1 β production of interferon (IFN)-treated patients with chronic hepatitis C who showed a loss of HCV RNA in their sera were equivalent to those of healthy controls (6.59±3.82, 6.58±2.03 ng/ml, respectively). PBMC positive for HCV negative-stranded RNA (replicative form of HCV) from asymptomatic HCV carriers and IFN-treated patients showed augmented IL-1 β production as compared with PBMC without HCV negative-stranded RNA. HCV infection of PBMC appears to lead to excessive LPS-induced production of IL-1 β in patients with chronic HCV infection.

Interleukin 2 and T-cell receptors in peripheral blood of patients with chronic hepatitis C virus infection

Abstract Studies were conducted to determine if CD3 (T-cell) associated antigen receptors (R) such as interleukin 2 (IL-2) and γδ participate in the pathogenesis of hepatitis C virus (HCV) infection. Peripheral blood T-cells bearing IL-2R α (CD25) or β (CD122) chain, and αβ or γδ were examined using two-color flow cytometry in 92 patients with various chronic HCV infection. CD25-positive T-cells were increased with the progression of the disease; patients with hepatocellular carcinoma (HCC) had the highest percentage of CD25 + T-cells, while CD 122 + T-cells were significantly higher in asymptomatic HCV carriers with normal serum ALT levels and mild to moderate chronic hepatitis. In HCC patients, a decrease in CD25 + cells and increase in CD 122+ cells were noted after hepatic resection or percutaneous ethanol injection. Asymptomatic carriers had higher γδ T-cells than in controls, and patients with chronic liver disease. The percentage of γδ T-cells became higher during IFN treatment in responders compared with nonresponders. The absolute number of T-cells studied here showed comparable results to those expressed as percentage in each patient group. There was no correlation between serum ALT values, HCV RNA levels, and the incidence of T-cell subsets. The findings suggest that IL-2R αβ chains on T-cells and γδ T-cell are associated with the pathogenesis of chronic HCV infection.

Quantitative analysis of antibody to hepatitis C virus envelope 2 glycoprotein in patients with chronic hepatitis C virus infection

The significance of circulating antibody to hepatitis C virus (HCV) envelope glycoprotein 2 (E2)/nonstructural protein 1 (NS1) glycoprotein was studied in 83 patients with chronic HCV infection diagnosed by polymerase chain reaction (PCR). E2/NS1 antibody was quantitatively examined by a passive hemagglutination test using recombinant E2/NS1 glycoprotein encompassing amino acids 388 to 664 of the HCV-H strain. The results were correlated with clinical and virological features such as genotypes and viremic levels assessed by a competitive reverse-transcription PCR assay. E2/NS1 antibody was found in 73 patients (88%), and its occurrence was related to viremic levels. E2/NS1 antibody titers were low in asymptomatic HCV carriers with low levels of viral replication; 9 of 17 such patients tested positive for E2/NS1 antibody (53%), compared with 64 of 66 chronic hepatitis C patients (97%) (P &lt; .01). A significant direct relationship was observed between viremic levels and E2/NS1 antibody titers (r = .52, P &lt; .01). Of the 13 patients with low viremic levels of &lt; 106 copies/mL, only 5 tested positive for E2/NS1 antibody (38%), whereas 68 of the 70 patients with viremic levels of &gt; or = 106 copies/mL had it (97%) (P &lt; .01). As for the relation to HCV genotypes, no difference was seen in E2/NS1 antibody titers among genotypes examined (1b, 2a, and 2b). These findings suggest that the E2/NS1 antibody tested exhibits no neutralizing activity in chronic HCV infection but may serve as a serological indicator of active virus replication.

Quantitative analysis of antibody to hepatitis C virus envelope 2 glycoprotein in patients with chronic hepatitis C virus infection

The significance of circulating antibody to hepatitis C virus (HCV) envelope glycoprotein 2 (E2)/nonstructural protein 1 (NS1) glycoprotein was studied in 83 patients with chronic HCV infection diagnosed by polymerase chain reaction (PCR). E2/NS1 antibody was quantitatively examined by a passive hemagglutination test using recombinant E2/NS1 glycoprotein encompassing amino acids 388 to 664 of the HCV-H strain. The results were correlated with clinical and virological features such as genotypes and viremic levels assessed by a competitive reverse-transcription PCR assay. E2/NS1 antibody was found in 73 patients (88%), and its occurrence was related to viremic levels. E2/NS1 antibody titers were low in asymptomatic HCV carriers with low levels of viral replication; 9 of 17 such patients tested positive for E2/NS1 antibody (53%), compared with 64 of 66 chronic hepatitis C patients (97%) (P < .01). A significant direct relationship was observed between viremic levels and E2/NS1 antibody titers (r = .52, P < .01). Of the 13 patients with low viremic levels of < 106 copies/mL, only 5 tested positive for E2/NS1 antibody (38%), whereas 68 of the 70 patients with viremic levels of > or = 106 copies/mL had it (97%) (P < .01). As for the relation to HCV genotypes, no difference was seen in E2/NS1 antibody titers among genotypes examined (1b, 2a, and 2b). These findings suggest that the E2/NS1 antibody tested exhibits no neutralizing activity in chronic HCV infection but may serve as a serological indicator of active virus replication. (Hepatology 1996 May;23(5):947-52)

Interferon gamma production by peripheral blood lymphocytes to hepatitis C virus core protein in chronic hepatitis C infection

Evidence suggests that cellular immunity to hepatitis C virus (HCV) core protein may be important in the pathogenesis of viral infection. Therefore, interferon gamma (IFN-γ) production by peripheral blood mononuclear cells (PBMC) derived from patients with chronic HCV infection (genotype 1b) was examined. The cellular immune response was evaluated with a recombinant HCV core fusion protein derived from a patient with genotype 1b. To identify the immunodominant epitopes, IFN-γ production in responders was also assessed with a panel of nine synthetic peptides that covered the entire core region. It was found that mononuclear cells from 24 (52%) of 46 patients with chronic liver disease responded to the core protein; asymptomatic HCV carriers demonstrated a lower response rate (14%, P &lt; .05). More important, individuals who had received IFN-α treatment and went into clinical and virological remission had a higher response rate (75%, P &lt; .05) compared with those with ongoing hepatitis whose treatment failed (31%). Of 25 patients whose mononuclear cells responded to HCV core protein, 18 had a significant response to one or more peptides; 12 patients reacted to a peptide mixture containing hydrophilic sequences. The core peptide amino acid sequence 141 to 160 was recognized in 9 patients. Interestingly, 7 of 8 patients bearing HLA DR 4 and w53 haplotypes recognized the peptide sequence 141 to 160. Thus, IFN-γ production of the mononuclear cell response appeared to be HLA DR restricted, and the responding cells were identified as CD4+ T cells. This study suggests the presence of immunodominant T cell epitopes within the HCV core protein in association with HLA DR phenotypes in patients with HCV-associated liver disease. (Hepatology 1995;22:1057-1064.).