Humoral immunoreactivity to HCV core antigen in patients with chronic hepatitis C.
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Chronic Disease↗
Biomedical subjects
G L Davis
Publications and source records attributed to G L Davis.
Serum interleukin 4 and interleukin 10 levels in patients with chronic hepatitis C virus infection.
BACKGROUND/AIMS: Immune-mediated mechanisms are believed to play an important pathogenetic role in chronic hepatitis C virus infection. Interleukin 4 (IL-4) and IL-10 are secreted by T helper-2 type cells (Th2) which may downregulate cell-mediated immune effector mechanisms important in the host defense against intracellular pathogens. This study aimed to determine Th2 cytokine levels in chronic hepatitis C virus infection. METHODS: Serum IL-4 and IL-10 levels were measured in 74 patients with chronic hepatitis C virus infection and 20 healthy controls. The expression of CD30 in liver, a marker that is preferentially expressed in Th2 cells, was also determined by immunohistochemical staining in 37 patients. RESULTS: Serum IL-4 and IL-10 were below the detection limit (5 pg/ml) in all 20 healthy controls. However, 36 patients (49%) had elevated serum IL-4 levels (range 5-106 pg/ml, p<0.001) and 23 patients (31%) had elevated serum IL-10 levels (range 5-37 pg/ml, p<0.05). There was no correlation between serum IL-4 and IL-10 levels. There was also no correlation between serum IL-4 and IL-10 levels and any of the clinical (age, gender, mode of acquisition), biochemical (serum alanine transaminase levels), virologic (viremia level, genotype), and histological parameters examined. Twenty of 37 liver biopsy specimens from patients with chronic hepatitis C virus infection showed occasional CD30+ lymphocytes, suggestive of Th2 phenotype. However, in 20 of the 37 patients with paired cryostat liver sections, IL-4 was not detected in any of these patients, suggesting that IL-4 was not produced in the liver in patients with chronic hepatitis C virus infection. CONCLUSIONS: This study showed that serum Th2 cytokines are elevated (but at a low level) in a proportion of patients with chronic hepatitis C virus infection. However, the elevated Th2 cytokine levels may represent a systemic response and not a result of increased local production within the liver.
Adult↗
Treatment of acute and chronic hepatitis C.
Interferon is currently the only available treatment for chronic hepatitis C but is effective in only about 40% of patients. Most of these responding patients relapse after short courses, so that sustained long-term viral-negative responses are uncommon (10% to 20%). However, longer treatment courses have significantly reduced relapse, thereby increasing sustained response rates. Furthermore, the combination of ribavirin with interferon shows promise for reducing relapse even further. The challenge for the future is to develop antiviral agents that will be effective in the large proportion of patients who do not respond to interferon.
Amantadine↗
Activation of tumor necrosis factor-alpha system in chronic hepatitis C virus infection.
Tumor necrosis factor-alpha (TNF-alpha) plays a central role in the host's immunomodulatory response to infective agents. To evaluate the TNF-alpha system in patients with chronic hepatitis C virus (HCV) infection, plasma, serum, and peripheral blood mononuclear cells (PBMC) were prospectively collected from 53 patients and 33 healthy control subjects. Circulating TNF-alpha and TNF receptors were assayed by their respective enzyme immunoassays. In addition, TNF-alpha mRNA was quantitated in PBMC using a branched DNA assay, and production of TNF-alpha by PBMC with and without lipopolysaccharide was also assessed. Patients with chronic HCV infection had a higher level of circulating TNF-alpha compared to healthy control subjects (9.62 +/- 6.01 vs 3.66 +/- 1.23 pg/ml, P < 0.001). They also had higher circulating levels of TNF receptors compared to control (CD120a: 3323 +/- 1267, pg/ml, N = 49 vs 1855 +/- 422 pg/ml, N = 33, P < 0.001; CD120b: 1290 +/- 650 pg/ml, N = 51, vs 863 +/- 207 pg/ml, N = 33, P < 0.001). Plasma TNF-alpha level correlated with circulating CD120a (r = 0.52, N = 49, P < 0.001) and weakly with CD120b (r = 0.32, N = 51, P = 0.02). Plasma TNF-alpha also correlated with markers of hepatocellular injury, including ALT (r = 0.34, N = 53, P = 0.01) and alpha-GST (r = 0.31, N = 43, P = 0.042), but not with serum HCV RNA levels. There was no difference in the TNF-alpha mRNA levels in PBMC between patients with chronic HCV infection (1.4 +/- 1.9 units/10[6] cells, N = 8) and healthy control subjects (2.1 +/- 1.4 units/10[6] cells, N = 8, P = NS). There was also no difference in the spontaneous production of TNF-alpha by PBMC (1 x 10[6] cells/ml) between patients with chronic HCV infection (14.2 +/- 36.5 pg/ml, N = 11) and healthy subjects (11.9 +/- 14.0 pg/ml, N = 14, P = NS). However, patients with chronic HCV infection produced more TNF-alpha upon stimulation with lipopolysaccharide compared to healthy control subjects (1278 +/- 693 pg/ml, N = 11, vs 629 +/- 689 pg/ml, N = 14, P < 0.05). These data indicate that the TNF-alpha system is activated in patients with chronic HCV infection.
Adolescent↗
Should we test hepatitis C virus genotype and viraemia level in patients with chronic hepatitis C?
Hepatitis C is a major health problem and at present, interferon-alpha is the only therapy of proven use. Two viral factors, namely HCV genotype and viraemia levels, have been studied extensively for their possible role in the clinical management of patients with chronic hepatitis C virus infection. This review attempts to summarize our current understanding of these two viral factors and provide recommendations as to how these two parameters should be used by general practitioners, practising gastroenterologists/hepatologists, and investigators in 1997.
Genotype↗
Variations of hepatitis B virus core gene sequence in Western patients with chronic hepatitis B virus infection.
Heterogeneity of the hepatitis B virus (HBV) core gene has been reported to be associated with the presence of active liver disease in Japanese patients with chronic HBV infection. This study evaluated the significance of HBV core gene heterogeneity in Western patients with chronic HBV infection. The hepatitis B virus precore/core gene from 45 patients (inactive:active liver disease ratio 16:29) was amplified from serum by polymerase chain reaction (PCR). Gel electrophoresis was employed to detect large deletions. The PCR amplicons from 13 patients (all HBV serotype adw but with a different spectrum of liver disease) were cloned and sequenced. Hepatitis B surface antigen (HBsAg) serotypes were tested by enzyme immunoassay (EIA) and hepatic expression of HBV antigens was assessed by immunohistochemistry. The HBV core gene was amplified from the serum of all 45 patients. Three patients had mixed infection with both precore mutant and wild-type HBV and all three had active liver disease. No patient had a large deletion of the HBV core gene. Hepatitis B virus core gene sequence variations were more common in the midcore region and there was no difference in the number of silent and missense substitutions between those with inactive and active liver disease. There was no correlation between the nucleotide or encoded amino acid substitutions and the clinical and biochemical parameters, including the subsequent response to interferon-alpha therapy (n = 37) or hepatic HBV antigen expression. Variation of the HBV core gene was not found to be preferentially associated with active liver disease in Western patients with chronic HBV infection. The pattern of hepatitis B core gene variation is in accord with the genomic organization of HBV.
Adult↗
Transforming growth factor-beta 1 in chronic hepatitis C.
Transforming growth factor-beta 1 (TGF-beta 1) has been implicated in mediating hepatic fibrogenesis and is known to have negative regulatory effects on the immune system. To analyse the effects of TGF-beta 1 in chronic HCV, serum samples were prospectively collected from 88 chronic hepatitis C virus (HCV) patients and 34 healthy controls. Total and biologically active TGF-beta 1, interleukin (IL)-4 and IL-10 were measured by enzyme-linked immunosorbent assay (ELISA). HCV RNA levels were quantified by branched DNA signal amplification pathway (bDNA), and HCV genotypes were determined by restriction fragment length polymorphism (RFLP) based on the 5'-untranslated region (UTR). Histological diagnosis was available in 87 patients, and liver sections from 80 other HCV patients were evaluated for hepatic expression of TGF-beta 1 using immunohistochemistry. Patients with chronic HCV infection had a higher level of TGF-beta 1, both total (817 +/- 464 ng ml-1) and biologically active forms (520 +/- 370 pg ml-1), compared with controls (total TGF-beta 1 183 +/- 105 ng ml-1, P < 0.001; active TGF-beta 1 290 +/- 140 pg ml-1, P < 0.01). There was no correlation between either total or biologically active TGF-beta 1 and clinical variables (age, gender, duration), liver biochemistry (serum alanine aminotransferase) or virological (HCV RNA level, genotype) parameters but there was a correlation between total TGF-beta 1 and Knodell scores (P = 0.03, n = 54). However, when individual histological parameters were analysed, only the fibrosis score showed significant correlation (P = 0.04, n = 54). Immunohistochemistry revealed that 62% of HCV patients had TGF-beta 1 present in sinusoidal cells. No correlation existed between hepatic expression of TGF-beta 1 and any histological parameters. A trend existed towards a correlation between total TGF-beta 1 and IL-4 (P = 0.059, n = 74) but not with IL-10. Therefore, the TGF-beta 1 system is activated in chronic HCV infection and may contribute towards hepatic fibrogenesis; in addition, the TGF-beta 1 system may interact with IL-4.
Adult↗
Effect of interferon-alpha and ribavirin therapy on serum GB virus C/hepatitis G virus (GBV-C/HGV) RNA levels in patients chronically infected with hepatitis C virus and GBV-C/HGV.
GB virus C/hepatitis G virus (GBV-C/HGV) is a newly described virus associated with hepatitis in humans, and GBV-C/HGV coinfection is common in patients chronically infected with hepatitis C virus (HCV). To determine the clinical impact of GBV-C/HGV infection in such patients and the effect of interferon-alpha and ribavirin therapy on serum GBV-C/HGV RNA levels, GBV-C/HGV RNA was detected and quantitated in serum samples from 62 chronically infected HCV patients by a combination of a qualitative nested reverse transcription-polymerase chain reaction and a newly developed quantitative branched DNA assay: 10 patients were positive for serum GBV-C/HGV RNA. There were no differences in the clinical, biochemical, and histologic features of the patients with GBV-C/HGV-HCV coinfection compared with those with HCV infection alone. Interferon-alpha treatment caused a marked but usually transient reduction in serum GBV-C/HGV RNA, and ribavirin had, at most, a modest antiviral effect.
Adult↗
Hepatitis B: diagnosis and treatment.
The hepatitis B virus (HBV), a member of the Hepadnaviridae family, was discovered 30 years ago. Since that time, clinical and basic research has led to a clear understanding of the epidemiology and natural history of infection and the pathogenesis of the resulting liver injury. Physicians are now able to accurately diagnose acute and chronic infection, though our understanding of viral quantitation and its impact on disease course and treatment response is evolving. Hepatitis B must now be considered a preventable disease, since acute infection can be effectively prevented by either passive or active immunization. However, when acute infection does occur, it evolves into chronic hepatitis or a chronic infectious carrier state in a variable proportion of cases, depending on the age and underlying immune competence of the patient. Chronic infection can be treated, though the effectiveness of available antiviral and immunomodulatory agents is less than complete. Finally, variants of the HBV are being recognized, and coinfection with the defective viroid known as hepatitis D (formerly delta agent) has been described.
Acute Disease↗
Modulation of hepatitis C virus quasispecies heterogeneity by interferon-alpha and ribavirin therapy.
To determine the effects of interferon-alpha (IFN-alpha) and ribavirin therapy on hepatitis C virus (HCV) quasispecies heterogeneity, 29 patients with chronic HCV infection treated with either IFN-alpha (n = 15), ribavirin (n = 7) or placebo (n = 7) were studied. HCV quasispecies heterogeneity was determined by single-strand conformational polymorphism (SSCP) analysis of the HCV E2 hypervariable region 1 (HVR1). For patients receiving IFN-alpha, HVR1 was amplified in 14 of 15 patients before, and in six of seven patients after therapy. After controlling the amount of amplicon loaded, a reduction in the number of SSCP bands was observed with IFN-alpha therapy (median number of SSCP bands per patient was eight before therapy and two after therapy). In the seven patients within each of the ribavirin- and placebo-treated groups, there was no significant difference in the viraemia level, number of SSCP bands per patient or the SSCP band pattern, before and after therapy. These findings suggest that at the doses given, IFN-alpha, but not ribavirin, exerts a selective pressure on HCV quasispecies heterogeneity.
Adult↗
Measuring quality of care in a psychiatric hospital using artificial neural networks.
This study investigates a new method of measuring quality of care. Taking place at a tertiary psychiatric hospital with 5,128 admissions from January 1989 through December 1995, this study uses artificial neural networks (ANNs) to predict hospital length-of-stay (LOS) and uses the standard deviation of LOS in a formula to measure quality of care, Q. ANNs are trained with data using unique patient identifiers and are compared with identical ANNs trained without these identifiers. These two types of ANNs make a LOS prediction, P, with a slightly different accuracies, and this fact is exploited in measuring Q. The authors defined U as the standard deviation of the difference between the actual and the predicted LOS of the ANNs with unique patient identifiers, and defined G as the standard deviation of the difference between the actual and the predicted LOS of the ANNs without using these unique identifiers. Dividing U, the variation of individual LOS patterns intertwined with systemic LOS patterns, by G, the variation of predominately systemic LOS patterns, yields the ratio U/G, in which systemic effects are factored out leaving a measure of the average severity of patient illness. Ratios that exceed unity are seen in the patients who are more severely ill. The formula for quality of care, Q, divides the best LOS prediction accuracy, P, which is inversely proportional to overall variation in the delivery system, by U/G, which is inversely proportional to quality of care, written as: Q = P/(U/G). Q reflects the patients' perspective because LOS is concrete and tangible to patients. The study took place during hospital downsizing (political change), a consent decree (policy change), new administrative and medical personnel (staffing change), and the introduction of clozapine and risperidone for schizophrenia (therapeutic change). These events had a predominantly positive impact on Q. The value of Q correlated well with the Joint Commission on Accreditation of Health Care Organizations (JCAHO) triennial evaluations. Some conclusions that emerged from this study: 1) System variation, reflected in the standard deviation of LOS, increased with frequent changes in top management. 2) There was a clear-cut beneficial effect of clozapine, and to a lesser extent of risperidone in schizophrenia, allowing more community placement. 3) With a dedicated professional staff quality of care can prevail despite increasing variation in LOS (systemic problems). 4) The number of hospital employees per Q unit halved when the overall hospital Q ranged from low to high values as a result of policy and staffing improvements, suggesting an increased efficiency of operation. 5) Q can be an objective outcome measure of quality care from the patients' perspective.
Efficiency, Organizational↗
Treatment of chronic hepatitis C.
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Acute Disease↗
Hepatitis C virus infection among health care workers.
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Health Personnel↗
Distribution of hepatitis C virus genotypes determined by line probe assay in patients with chronic hepatitis C seen at tertiary referral centers in the United States. Hepatitis Interventional Therapy Group.
OBJECTIVE: To 1) verify the validity of a new line probe assay for hepatitis C virus (HCV) genotyping and 2) determine the distribution of HCV genotypes and the association between HCV genotype and clinical variables in patients with chronic hepatitis C seen in tertiary referral centers in the United States. DESIGN: Retrospective cross-sectional analysis. PATIENTS: 438 patients with chronic hepatitis C from 10 tertiary referral centers. MEASUREMENTS: The validity of the line probe assay was first verified against a panel of serum specimens that had previously been characterized by six different HCV genotyping methods. Specimens from all 438 patients were then genotyped using this line probe assay. The associations between HCV genotype and clinical variables were examined using analysis of variance. Pairwise testing was used when the F test showed a statistically significant difference. Nonparametric alternatives were used for variables for which normality could not be assumed. RESULTS: The line probe assay was quick and reproducible, and it showed good concordance with other tests. In our sample, the proportions of patients with HCV types 1, 2, 3, and 4 were 71.5%, 13.5%, 5.5%, and 1.1%, respectively. Subtypes 1a and 1b were seen in approximately equal proportions of patients with HCV type 1. Mixed infection was detected in 3.7% of specimens, and 4.8% of specimens either had negative results on polymerase chain reaction or could not be typed. A higher proportion of patients with HCV type 1 than of patients with HCV-type 1 had acquired HCV through transfusion of blood products (50% compared with 25%; P < 0.001). Patients with HCV type 1 also had a longer estimated duration of infection compared with patients with HCV type 3 (P = 0.004) and type 4 (P = 0.049). Disease activity did not differ among patients infected with HCV types 1, 2, or 3. Levels of viremia were similar in patients with HCV types 1, 2, or 3, but patients with HCV type 4 had a lower level of viremia than did patients with HCV type 1 (P = 0.047). CONCLUSIONS: The line probe assay can be used in patients with chronic HCV infection in the United States. In patients with chronic hepatitis C referred to tertiary centers in the United States, type 1 is the most common HCV genotype. Disease activity and viremia levels do not differ among patients chronically infected with HCV types 1, 2, or 3.
Adolescent↗
Clinical implications of viral quasispecies heterogeneity in chronic hepatitis C.
To determine the clinical significance of viral quasispecies heterogeneity, 59 patients with chronic hepatitis C were studied using singlestranded conformational polymorphism (SSCP) analysis of the HCV E2 hypervariable region 1 (HVR1); of these, 48 were subsequently treated with interferon-alpha. The SSCP method was validated using clones of known nucleotide sequence. HVR1 was amplified in 54 of 59 (92%) patients. The median number of SSCP bands per sample was 6 (range: 2-12). Increased quasispecies heterogeneity correlated with the estimated duration of HCV infection (P < 0.05), parenteral-acquired HCV infection (vs. sporadic, P < 0.05), serum HCV RNA levels (P < 0.05), and HCV genotype 1 infection (P < 0.05), but not with age, serum AST, ALT, or Knodell score. Patients who had complete and sustained response to interferon-alpha (n = 11) had lower pre-treatment quasispecies heterogeneity compared to patients who had complete response with relapse (n = 18, P < 0.05) or no complete response (n = 16, P < 0.01). However, multivariate analysis revealed that HCV viremia was a stronger predictor of response to interferon-alpha. These findings indicate that the estimated duration of HCV carriage, serum HCV RNA levels, and HCV type 1 are important determinants for the evolution of HCV quasispecies heterogeneity; and that increased HCV quasispecies heterogeneity is another marker associated with a poor subsequent response to interferon-alpha.
Adult↗
Hepatic expression of hepatitis C virus RNA in chronic hepatitis C: a study by in situ reverse-transcription polymerase chain reaction.
Hepatitis C virus (HCV) replicates at a low rate and this makes its detection and intrahepatic localization difficult. To evaluate the clinical implications and effect of interferon alfa (IFN-alpha) therapy on hepatic expression of HCV RNA, HCV RNA was detected by in situ reverse-transcription polymerase chain reaction (IS-RT-PCR) in formalin-fixed paraffin-embedded liver sections from 26 patients with chronic hepatitis C. Results were compared with RT-PCR of HCV RNA extracted from liver sections/tissue. Twenty-four paired post-IFN-alpha treatment biopsy specimens were also assessed. Using RT-PCR of the extracted RNA as a positive standard and non-HCV liver sections as the negative standard, the sensitivity and specificity of IS-RT-PCR were 69% and 100%, respectively. HCV RNA was detected in the cytoplasm of hepatocytes (median, 5% hepatocytes positive; range, 0 to 35%) and very occasionally in infiltrating mononuclear cells. There was no correlation between hepatic expression of HCV RNA and the clinical, biochemical parameters, total and activity scores of histology activity index. Presence of HCV RNA in liver as detected by IS-RT-PCR was associated with higher serum HCV RNA levels (4.9 x 10(6) vs. 0.4 x 10(6) genome Eq/mL, P < .01). There was no difference in the pretreatment proportion of HCV RNA-positive hepatocytes among patients with different biochemical responses to IFN-alpha therapy. In the posttreatment samples, HCV RNA was undetectable by IS-RT-PCR in 16 of 24 patients (P < .01), including all 4 patients who had complete and sustained response (SR). We conclude that HCV RNA was detected by IS-RT-PCR in 0 to 35% of hepatocytes in patients with chronic HCV infection, detection of HCV RNA in liver by IS-RT-PCR was associated with higher viremia levels and IFN-alpha therapy reduced hepatocytic expression of HCV RNA.
Adult↗
Response to higher doses of interferon alfa-2b in patients with chronic hepatitis C: a randomized multicenter trial. Hepatitis Interventional Therapy Group.
To evaluate response rates to 3, 5, or 10 million units (MU) of interferon alfa-2b, given thrice weekly, and to determine whether higher doses of interferon increase the likelihood or durability of the response, a multicenter, randomized trial was performed at nine academic medical centers in the United States. Two hundred forty eight patients with chronic hepatitis C were randomized to receive 3, 5, or 10 MU of interferon alfa-2b thrice weekly for 12 weeks. Based on the alanine aminotransferase (ALT) response at treatment-week 12, the patients were rerandomized to additional therapy at the same or at increased doses for an additional 12 to 36 weeks; in the case of no response to the highest dose, the patients were discontinued from the study. Serum ALT concentrations and liver histology were measured. The overall complete response rates to 3, 5, or 10 MU were not different at treatment-week 12 (31% vs. 42% vs. 40%, not significant). The majority of week-12 responders continued to respond during additional treatment. When the treatment was discontinued, 15.4% to 19.0% of patients maintained their response. Of the nonresponders to 3 MU at week 12, who were continued on 3 MU for an additional 12 weeks, none responded. However, response to additional therapy occurred in 12% of week-12 nonresponders, whose dose was escalated from 3 or 5 MU to 10 MU. The only baseline features associated with the treatment response were the absence of fibrosis or cirrhosis on the pretreatment liver biopsy and viral genotype. We conclude that the initial response to interferon in patients with chronic hepatitis C is not increased by treatment with higher doses of the drug. Patients who do not respond to 3 MU by treatment-week 12 will not respond with continued therapy at that dose; however, a proportion of patients who do not respond to 12 weeks of treatment with 3 or 5 MU may respond to higher doses. Although the long-term sustained response rates are marginally increased with interferon doses above 3 MU three times per week, the side effects are difficult to tolerate. The analysis of baseline factors in relation to response identified no single baseline factor associated with a low-enough response rate to warrant withholding interferon therapy from patients with chronic hepatitis C.
Adolescent↗
Modeling therapeutic benefit in the midst of uncertainty: therapy for hepatitis C.
Randomized, double-blind, controlled clinical trials are the gold standard for medical therapy. When a disease is rare or slowly progressive over many years, such a trial may not be feasible. Decision analysis provides a bridge between current studies with short-term surrogate markers and a large, longitudinal clinical trial. With decision analysis, results of current studies can be summarized and the outcome of a long-term study projected under explicit assumptions. Chronic hepatitis C is a disease that is slowly progressive, and the requirements of a longitudinal clinical study could be prohibitive. Therefore, we review the basic steps of decision analysis, apply these steps to two recent decision analyses evaluating the use of interferon-alpha2b (IFN) in the treatment of chronic hepatitis C, and discuss possible implications of decision modeling for this disease. The estimated marginal cost per year of life gained from IFN therapy ranged from approximately $3000 to $55,000 in these two studies. The wide range is based on different estimates of treatment costs and disease progression. This analysis has identified gaps in the current knowledge regarding the natural progression of hepatitis C and has established criteria to evaluate new developments and their impact on chronic hepatitis C.
Chronic Disease↗