Intrahepatic HCV RNA loads in 37 HIV-HCV co-infected patients with controlled HIV infection

Serum and intrahepatic hepatitis C virus (HCV) RNA were measured in 37 HIV-HCV co-infected patients with controlled human immunodeficiency virus (HIV) infection and correlated with clinical, biological, and histological parameters. Thirty-seven interferon-naive patients underwent liver biopsy. HCV-induced activity (A) and fibrosis (F) were evaluated with METAVIR score. The 37 patients included had HIV plasma loads < 10,000 copies/ml, CD4(+) count > 250/microl. All the patients but two were receiving antiretroviral treatment. Liver tissue and sera were used for measurement of HCV RNA by the Cobas Amplicor HCV Monitor. All patients had serum and liver HCV RNA, and both levels were correlated (r = 0.47; P = 0.003). Intrahepatic HCV load did not depend on age, sex, duration of HCV infection, CD4(+), HCV genotype, or fibrosis. AST levels correlated with intrahepatic HCV load (r = 0.52; P = 0.001). Patients with METAVIR A1/A2 had significantly lower levels of liver HCV-RNA than were found in patients with METAVIR A3 (P = 0.026). Highly active antiretroviral therapy (HAART) including protease inhibitors(PI)-treated patients had significantly lower intrahepatic HCV load (P = 0.04). A weak but significant correlation between serum and liver HCV RNA was found. The amount of hepatic HCV RNA was correlated with AST levels, histological activity, but not with HCV genotype or fibrosis. The immune improvement associated with PI regimens could help reduce HCV load, supporting a protective effect of PI-induced immune restoration.     

Role of interleukin 28-B in the spontaneous and treatment-related clearance of HCV infection in patients with chronic HBV/HCV dual infection

The purpose of this investigation was to evaluate the role of IL28-B polymorphism in the clearance of hepatitis C virus (HCV) in chronic hepatitis B virus (HBV)/HCV coinfection during a long-term follow-up. Thirty-four consecutive patients with HBV surface antigen (HBsAg)-positive/anti-HCV-positive chronic hepatitis were retrospectively enrolled at their first liver biopsy (LB). For all patients, a documented clinical, serological and virological follow-up of at least 3 years (range 3–16 years) after LB and a sample of whole blood for genetic evaluation were available. Of the 24 patients with detectable serum HBV-DNA and HCV-RNA at their first observation, three cleared both HBV-DNA and HCV-RNA, 12 HCV-RNA and five HBV-DNA. Of the seven HBV DNA-positive/HCV RNA-negative patients at enrolment, three cleared HBV-DNA and one remained HBV DNA-positive and became HCV RNA-positive. All three HBV DNA-negative/HCV RNA-positive patients remained unchanged. Compared with the 12 patients with HCV persistence, the 15 patients who cleared HCV were younger, had lower serum alanine aminotransferase (ALT), HCV load, and histological activity index (HAI) and fibrosis score, more frequently had IL28-B CC variant, had been receiving an interferon-based treatment and less frequently cleared serum HBV-DNA. To investigate the relationship between the IL28-B variants and clearance of HCV, excluding the confounding effect of interferon-based treatment, the Mantel–Haenszel test was used, which indicated an association between HCV clearance and IL28-B variants (p?=?0.009). In chronic HBV/HCV coinfection, a long-term follow-up showed a frequent spontaneous or treatment-related clearance of active replication of one or both viruses and identified the IL28-B CC genotype as an independent predictor of HCV clearance.     

HCV RNA in patients with chronic hepatitis C treated with interferon-α

In order to assess the efficacy of interferon-α on hepatitis C viral RNA in patients with chronic hepatitis C, we analyzed the levels of HCV RNA in sera and liver tissues of 16 patients pre- and posttreatment using a semiquantitative polymerase chain reaction method. Fifteen of 16 patients were positive for anti-HCV antibodies by four-antigen recombinant immunoblot assay (4-RIBA). Only two patients demonstrated normalization of ALT in response to interferon; three patients showed a partial response. Only one patient from the partial responder group displayed a significant reduction of HCV RNA level posttreatment. In the nonresponder group, several patients, although their ALTs remained elevated, demonstrated significant decreases in HCV RNA levels in either serum or liver in response to interferon. Our data suggest that interferon treatment of chronic hepatitis C may not be effective in eradicating HCV infection and a reduction in ALT is infrequently associated with a decrease in HCV RNA level in either serum or liver. Cessation of treatment is frequently associated with the recrudescence of HCV replication and disease. © 1993 Wiley-Liss, Inc.     

慢性丙型肝炎患者血清细胞因子水平的变化及意义

目的:检测慢性丙型肝炎患者血清细胞因子IL-2、IFN-г、IL-5、IL-6、IL-12P70和P40水平,探讨其与患者血清ALT水平、HVC RNA载量、HCV基因型及干扰素疗效的关系。方法:检测30例健康对照者和30例慢性丙型肝炎患者干扰素治疗前后血清IL-2、IFN-г、IL-5、IL-6、IL-12P70和P40的含量,比较干扰素治疗应答组和无应答组之间细胞因子水平的差异及上述细胞因子水平与血清ALT水平、HCV基因型、HCVRNA载量等的关系。血清细胞因子检测应用ELISA法,HCV基因分型应用直接测序法,HCVRNA载量采用荧光定量PCR法。结果:与健康对照组相比,慢性丙型肝炎患者血清IL-2含量明显降低,IL-5和IL-12P40明显生高;血清IL-6含量与血清ALT水平呈正相关,与RNA载量呈负相关;HCV基因型1型患者血清IL-6含量明显高于2型,其他基因型和亚型之间细胞因子水平均无显著性差异;干扰素治疗的持续应答率为46.7%,应答组和无应答组治疗前血清细胞因子水平均无显著性差异,但应答组治疗结束时IFN-γ含量较治疗前明显升高。结论:血清Th1/Th2细胞因子水平失衡与丙型肝炎的慢性化和肝脏炎症活动相关;干扰素治疗前血清Th1/Th2细胞因子水平与干扰素治疗效果无关,不能对疗效进行预测,干扰素诱导的Th1细胞优势反应与持续应答有关。     

Factors affecting serum concentrations of hepatitis C virus (HCV) RNA in HCV genotype 1-infected patients with chronic hepatitis

The serum concentration of hepatitis C virus (HCV) RNA is usually stable (4 to 8 log(10) IU/ml) in untreated patients with chronic hepatitis C. While this baseline HCV RNA concentration ([HCV RNA](BL)) is predictive of a sustained virologic response to treatment, its determinants are only partially identified. We therefore analyzed the baseline characteristics of 2,472 HCV genotype 1-infected patients to identify correlations with gender, age, race, weight, body mass index (BMI), HCV acquisition mode, HCV subtype, alanine aminotransferase concentration, or histopathologic changes in the liver. After separation of the data according to four [HCV RNA](BL) groups (< or =5.0, >5.0 to 5.6, >5.6 to 5.9, and >5.9 log(10) IU/ml), we determined that increasing [HCV RNA](BL) correlated (P < 0.05) with increasing proportions of patients who were male, >40 years of age, or heavier (a weight of >85 kg or a BMI of >27 kg/m(2)). Histologic activity index (HAI) data were available for 1,304 of these patients: increasing [HCV RNA](BL) correlated with higher fibrosis and necrosis-inflammation scores. As a continuous variable, [HCV RNA](BL) correlated with age, gender, weight (continuous or < or =85 versus >85 kg), BMI (continuous or < or =27 versus >27 kg/m(2)), subtype, fibrosis score, and necrosis-inflammation score; however, multiple-regression analysis yielded P values of <0.1 only for age, gender, BMI (< or =27 versus >27 kg/m(2)), and fibrosis score. While our findings are suggestive of a role for these factors in maintenance of the pretreatment state of HCV infection, the multiple-regression model accounted for only < or =4.6% of the [HCV RNA](BL) differences between individuals (R(2) = 0.046 for 1,304 patients with HAI scores; 0.043 for all 2,472 patients).     

Genotypes and titers of hepatitis C virus for predicting response to interferon in patients with chronic hepatitis C

Interferon induces remission in about 50% of patients with chronic hepatitis C, but it is difficult to predict which patients will respond. Host and viral factors were evaluated for correlation with response to interferon in patients with chronic hepatitis C. Recombinant interferon alpha-2b with a total dose of 480-560 million units was given to 136 patients, of whom 74 (54%) responded. Genotypes of hepatitis C virus (HCV) in sera, I, II, III, IV, and V, were determined by poly-merase chain reaction (PCR) with type-specific primers. In 72 patients, pretreatment levels of HCV RNA were titrated by PCR in serial tenfold dilutions of RNA extracted from serum. Response to interferon occurred in 34 (40%) of 85 patients infected with HCV of genotype II, less frequently than in 22 (85%) of 26 with genotype III (P < 0.001) or in 7 (70%) of 10 with genotype IV. Of 51 patients with genotype II HCV, 6 of 8 (75%) with HCV RNA titers <10⁶ responded, more frequently than 4 of 43 (9%) with titers ≥ 10⁶ (P < 0.001). Responders were younger than non-responders (45.7 ± 11.7 vs. 50.3 ± 9.6 yr) and had received transfusions less frequently (26/74 or 35% vs. 37/62 or 60%, P < 0.01). Response to interferon correlated inversely with the severity of liver histopathology. These results indicate that response to interferon is influenced by HCV genotypes and pretreatment levels of HCV RNA in serum. © 1994 Wiley-Liss, Inc.     

Total HCV core antigen assay. A new marker of HCV viremia and its application during treatment of chronic hepatitis C

The present study assesses the clinical usefulness of the hepatitis C core antigen assay for monitoring of patients being treated for chronic hepatitis C virus (HCV) infection. Eighty-six serum samples were selected at random from 16 patients and levels of HCV RNA and HCV core antigen were determined simultaneously and in parallel to compare both techniques. The data obtained were compared by Pearson’s correlation and the coefficients calculated by Fisher transformation and by calculating the difference and standard error. A good linear correlation was observed between both techniques. Maximum correlation, with significant difference, was found between patients infected with the 1a genotype and other genotypes. In conclusion, the HCV core antigen assay is useful for the diagnosis of early infection; however, its use for determining the exact timing of viral elimination during treatment is clearly unsuitable.     

Longitudinal study of hepatitis C viremia in chronic hepatitis C

Serial serum samples from 20 untreated patients with chronic hepatitis C virus (HCV) infection were tested for HCV RNA by a nested polymerase chain reaction assay using primers from the highly conserved 5′ noncoding region to determine the relationship between hepatitis C viremia and the activity of liver disease during the natural course of chronic HCV infection. Semiquantitation of serum HCV RNA level was achieved by testing serial 10-fold dilutions of RNA extracts to determine the end-point titer. All the patients were HCV RNA positive at presentation. There was a poor correlation between the initial HCV RNA titer and serum transaminase levels. All patients except one were persistently HCV RNA positive during a follow-up period of 1.5-15 years, although 17 (85%) had periods of normal or near-normal transaminase levels. There was no correlation between changes in the serum transaminase levels and HCV RNA titer. Patients with chronic HCV infection have persistent viremia despite fluctuations in ALT levels.     

Uselessness of liver biopsy in patients with hepatitis C virus chronic infection and persistently normal aminotransferase levels

This case-control study evaluated the real need for liver biopsy in subjects with persistently normal aminotransferase values over a long period by comparing the histological features of these subjects with those of patients with abnormal aminotransferase values. We considered as "Cases" all 32 consecutive anti-HCV/HCV-RNA positive subjects with at least eight normal serum ALT values during the last twelve months; for each "Case", we selected as a "Control" one anti-HCV/HCV-RNA positive patient with at least two abnormal serum ALT values during the last twelve months. The Cases and Controls were matched for age ( 5 years) and sex. In the Case group, 1 subject showed normal liver tissue, 18 minimal chronic hepatitis (CH) and 13 mild CH. In the Control group, 7 subjects showed minimal CH, 19 mild CH, 3 moderate CH, 1 severe CH and 2 cirrhosis. The subjects in the Control group showed a significantly higher HAI score (5.39+2.81) than those in the Case group (2.96+1.62, p < 0.001). The subjects in the Control group more frequently showed a fibrosis score greater than 1 (28.1%) compared to the Case group (9.4%; p<0.05). Finally, steatosis was more frequent and more severe in the Control group than in the Case group (respectively, 78.1% vs 50%, p < 0.05; and 1.47+1.16 vs 0.6+0.71, p < 0.001). The HAI and fibrosis scores did not correlate with the ALT value, HCV genotype or HCV viral load in either the Case or Control group. Our findings showed that the subjects with a persistently normal serum ALT value had minimal or mild chronic hepatitis, thus demonstrating that a liver biopsy is not indicated for these subjects.     

Assessment of viral loads in patients with chronic hepatitis C with AMPLICOR HCV MONITOR version 1.0, COBAS HCV MONITOR version 2.0, and QUANTIPLEX HCV RNA version 2.0 assays

The correlation between response to antiviral therapy and pretreatment viral load in patients with chronic hepatitis C has prompted the development of quantitative assays to measure viral load. The aim of our study was to assess the clinical relevance of the newly developed semiautomated PCR system COBAS HCV MONITOR version 2.0 in comparison with (i) the AMPLICOR HCV MONITOR version 1.0 assay, which underestimates RNA concentration of hepatitis C virus (HCV) genotypes 2 to 6, and (ii) the QUANTIPLEX HCV RNA version 2.0 assay, which achieves equivalent quantification for each HCV genotype, with samples from 174 patients diagnosed with chronic hepatitis C before therapy. The level and range of quantification measured with AMPLICOR HCV MONITOR version 1.0 were 1 log lower than when measured with the COBAS HCV MONITOR version 2.0, at 0.261 x 10(6) RNA copies/ml (range, 0.001 x 10(6) to 2.50 x 10(6) RNA copies/ml) and 4.032 x 10(6) RNA copies/ml (range, 0.026 x 10(6) to 72.6 x 10(6) RNA copies/ml), respectively. The two assays showed a poor correlation (r(2) = 0.175). The level and range of quantification were similar when measured with the COBAS HCV MONITOR version 2.0 and QUANTIPLEX HCV RNA version 2.0 assays, at 3.03 x 10(6) RNA copies/ml (range, 0.023 x 10(6) to 72.6 x 10(6) RNA copies/ml) and 4.91 Meq/ml (range, 0.200 to 49.5 Meq/ml), respectively. The two assays showed a strong correlation (r(2) = 0. 686) for each HCV genotype. The duration of treatment (6 or 12 months) is modulated according to HCV genotype and viral load. Our results indicate that COBAS HCV MONITOR version 2.0 and QUANTIPLEX HCV RNA version 2.0 assays showing an equal dynamic range for each HCV genotype are suitable tools to assess patients before therapy.     

Analysis of prognostic factors in therapeutic responses to interferon in patients with chronic hepatitis C

The genotype of hepatitis C virus (HCV) and the amount of HCV RNA are often used to predict the efficacy of interferon (IFN) therapy on chronic hepatitis C. In addition to these factors, there may be several factors related to the host. Therefore, the authors undertook a retrospective study in which physical findings and laboratory data before therapy were evaluated by multiple logistic analysis. Two-hundred and five cases with chronic hepatitis C treated with interferon were analyzed in this study. Sustained virological response was observed with 68 cases. Multiple logistic analysis was performed with 29 explanatory variables including HCV genotype, HCV RNA, IFN types, and total dose, along with gender, age, alcohol consumption, body mass index (BMI), histological findings of liver biopsy, platelet counts, and laboratory data of serum enzymes. Analysis on the factors that correlated well with therapeutic efficacy revealed that genotype 2a, 2b showed higher therapeutic responses than genotype 1b with reference to HCV genotypes, and higher IFN dose or lower HCV RNA levels gave better results. With reference to host factors, higher total protein level, lower levels of BMI, total bilirubin, and aspartate aminotransferase were highly correlated with therapeutic efficacy. HCV genotypes and HCV RNA levels have been already identified as prognostic factors. However, the high correlation values of BMI and the total protein level are new findings. It is suggested that probability estimation of therapeutic effects using the logistic regression equation may be a good tool for predicting therapeutic efficacy of IFN therapy on individual cases.     

Simultaneous evaluation of lymphocyte subpopulations in the liver and in peripheral blood mononuclear cells of HCV-infected patients: relationship with histological lesions

Intrahepatic lymphocytes are believed to be involved in the immunopathogenesis of hepatitis C virus (HCV) infection and the evolution of HCV-induced hepatitis. In the present study, we examined the three main intrahepatic lymphocyte subsets, namely CD3+CD56- conventional T lymphocytes, CD3+CD56+ natural T (NT) lymphocytes and CD3-CD56+ natural killer (NK) lymphocytes in HCV-infected patients. The proportion of each lymphocyte subset was evaluated both in liver biopsies and in samples of peripheral blood lymphocytes (PBL) by flow cytometry in 21 patients with histologically proven chronic hepatitis C. Simultaneously, alanine aminotransferase (ALT) levels, viral load and histological lesions were assessed. Neither NT nor NK populations correlated with any biochemical, viral or histological parameters. Furthermore, Valpha24+ NT lymphocytes showed no preferential enrichment in the liver of HCV-infected patients. Regarding conventional T lymphocytes, a highly significant linear correlation was found between intrahepatic CD3+CD56- T lymphocytes and the Knodell score, a numerical score for assessing histological activity and fibrosis (r = 0.715, P < 0.0001) and more specifically with the periportal necrosis parameter, which is the main lesion of chronic hepatitis C. In addition, analysis of the peripheral compartment revealed a high correlation between values of CD3+CD56- lymphocytes and both Knodell score (r = 0.624, P = 0.003) and serum ALT levels and again with periportal necrosis. The strong correlation between the proportion of peripheral CD3+CD56- conventional T lymphocytes and the severity of hepatic lesions leads us to propose that evaluation of this accessible peripheral population could be used as an indicator test for the severity of histological lesions in chronic hepatitis C. Abbreviations:     

Hepatitis C plasma viral load is associated with HCV genotype but not with HIV coinfection

The influence of human immunodeficiency virus (HIV) coinfection and hepatitis C virus (HCV) genotype distribution on HCV viral load and alanine amino transferase (ALT) levels in chronically infected patients remains unclear. In the present study, serum samples from a group of haemophiliac patients were investigated retrospectively. HCV geno- and subtyping was carried out using the Inno line probe assay (Inno LIPA, Innogenetics, Zwijnaarde, Belgium) in 87 patients positive by HCV RT PCR. Of these patients, 31 (35.6%) were HIV coinfected. HCVRNA was quantified with the HCV Monitor kit (Roche, Basel, Switzerland) in 43 patients (22 HIV-negatives, 21 HIV-positives). The most prevalent genotypes were 1 (n = 52) and 3a (n = 16) followed by genotype 2 (n = 9) and 4 (n = 3). Mixed infections were detected in 7 patients. Of genotype 1 positive samples, 24 and 23 were classified as subtype a and b, respectively. Five samples could not be subtyped. Although higher mean values of ALT were observed in genotype 1 infected patients, there was no statistically significant association between HCV genotype or subtype and liver enzymes (P > 0.05). On the other hand, statistically significant higher HCV RNA titres were observed in haemophiliacs infected with HCV genotype 1 in comparison to those infected with other genotypes (P < 0.01). No relationship was found between the presence of HIV coinfection and viral load of HCV RNA. There was no evidence that HCV infection had a more severe outcome in HIV-positive patients who had been infected with HIV and HCV more than ten years ago, even in those with very low CD4+ cell counts. No clear association between high ALT levels and large amounts of viral RNA was observed. In conclusion, a large viral load is associated with HCV genotype 1 infection; HIV coinfection has no clear effect on the intensity of HCV replication. An ongoing prospective study will evaluate the respective role of viral load, genotype, HIV coinfection and ALT level in the response to interferon therapy. © 1996 Wiley-Liss, Inc.     

Glucagon test for Doppler sonography measurement of portal flow in chronic HCV infections

Purpose - To evaluate whether Doppler sonography measurement of portal flow velocity (PFV) after glucagon injection can be useful in assessing the severity of liver damage in chronic HCV infection. Methods - Forty-five patients (32 males and 13 females; mean age 54.1 14.8 years) with biochemical (raised serum ALT levels), virological (positive serum HCV RNA test) and histological (liver biopsy) evidence of chronic HCV infection were included in the study. According to hepatitis staging (degree of liver fibrosis), as assessed by Knodell histological activity index, patients were divided into three groups: group 1 (n.=17), with no or mild fibrosis (fibrosis score: 0-1); group 2 (n.=11), with severe fibrosis (score: 3); and group 3 (n.=17), with liver cirrhosis (score: 4). For sonographic measurements of PFV, a Doppler ultrasound multi-purpose equipment and a convex 3.5 MHz probe were used. All patients were examined after an 8-hour fast, in supine position, 10 min before (baseline), as well as 5 and 10 min after, intravenous administration of 1 mg of glucagon chloride (Novo Nordisk). Statistical analysis was performed by ANOVA test, Bonferroni t test and Spearman rank correlation test. Results - No significant differences were found in mean basal PFV of group 1 (19.4 2.4 cm/sec), group 2 (20.1 3.6 cm/sec) and group 3 (17.5 3.7 cm/sec) (p > 0.05). Five minutes after glucagon injection, all the three groups showed a significant increase in PFV (25.6 4.8,23.7 4.0 and 19.5 5.0 cm/sec, respectively; p < 0.05 vs baseline). The peak increase in PFV after glucagon injection was significantly higher in group 1 (7.9 3.7 cm/sec; 40.7% of basal value) than in group 2 (4.5 3.9 cm/sec; 22.4%) (p < 0.05) and in group 3 (2.7+2.3 cm/sec; 15.4%) (p < 0.05). A significant (p< 0.001) inverse correlation was also found between the patients fibrosis scores and peak increments of PFV induced by glucagon. Conclusions - In some patients with chronic HCV infection, Doppler sonography measurement of PFV after glucagon injection can be useful, in combination with other non invasive ultrasound investigations, both in staging of liver disease and in monitoring the progression of liver histological damage.     

Spontaneous elimination of serum hepatitis C virus (HCV) RNA in chronic HCV carriers: a population-based cohort study

The natural course of hepatitis C virus (HCV) infection has not been fully elucidated. To investigate whether HCV is spontaneously eliminated in chronic carriers, a long-term population-based cohort study was conducted on 435 chronic HCV carriers. Individual characteristics, serum HCV RNA, and liver function tests were analyzed, and ultra sonography (US) was performed in all subjects. Subjects were followed up for 7.2 +/- 2.4 years (mean +/- SD). Serum HCV RNA was spontaneously eliminated in 16/435 (3.7%) individuals during this period; thus, the incidence of spontaneous elimination of serum HCV RNA was 0.5%/year/person. Multivariate analysis revealed that both a low value of ZTT and no US finding of chronic liver disease were associated with spontaneous viral elimination in HCV carriers. Three of these 16 individuals had chronic hepatitis, and 13 of them had normal ALT levels. When the neutralization of binding (NOB) assay that evaluates inhibition of the HCV envelope-2 protein binding to human cells was examined using sera from these 16 individuals, the NOB antibody was detected in only 3 cases with chronic hepatitis. These results suggest that serum HCV RNA is spontaneously eliminated in chronic HCV carriers in a population, and that the development of NOB antibody is associated with a natural resolution of chronic hepatitis in the minority of them.     

吉林省延边地区朝鲜族与汉族HCV基因型特征分析

目的分析吉林省延边地区朝鲜族与汉族丙型肝炎病毒（HCV）基因型特征。方法采用荧光定量PCR方法和探针反向杂交技术对延边地区收治的62例朝鲜族和57例汉族慢性丙型肝炎患者进行HCV病毒载量检测和HCV基因型分析,比较HCV基因型在朝鲜族与汉族之间的分布差异,并分析HCV基因型与病毒载量、2型糖尿病和肝病严重程度之间的相关性。结果朝鲜族HCV基因型显示,1b型占45．16％（28／62）、2a型占38．71％（24／62）、未分型占16．13％（（10／62）;汉族HCV基因型显示,1b型占45．61％（26／57）,2a型占40．35％（23／57）,未分型占14．14％（8／57）,朝、汉族之间各基因型分布差异无统计学意义（P〉0．05）。HCV各基因型之间HCV病毒载量差异和合并2型糖尿病分布差异之间无统计学意义（P〉0．05）,而HCV1b型在中、重度慢性丙型肝炎患者与轻度慢性丙型肝炎患者中所占的比例差异具有统计学意义（P〈0．05）。结论①吉林省延边地区HCV基因型中以1b型最多,2a型次之,还有少数其他基因型;②HCV基因型在朝、汉民族之间分布无差异;③HCV基因型与HCV—RNA载量无关;④HCV基因型在合并糖尿病者与未合并糖尿病者之间分布无差异;⑤1b型HCV感染者病情相对较重。     

Histological Damage in Chronic Hepatitis C Is Not Related to the Extent of Infection in the Liver

It has not been completely elucidated whether the liver injury induced by the hepatitis C virus (HCV) is due to direct cytopathic damage or to an immune-mediated response against HCV-infected hepatocytes. In this work, we have determined the percentage of HCV-infected hepatocytes, the histological activity index, and the viremia levels in chronically HCV-infected patients with different grades of liver injury to investigate any possible correlation between them. For that purpose, liver biopsies from 27 patients with HCV chronic hepatitis were analyzed by in situ hybridization. This technique revealed that the percentage of infected hepatocytes ranged from 0.04% to 83.6%. Regarding the viremia levels, HCV RNA concentration ranged from 1.8 x 10(3) to 1.4 x 10(6) genome copies/ml. A significant correlation (r = 0.54; P = 0.003) between the percentage of infected hepatocytes and the viremia levels was found. In contrast, no correlation was observed between the percentage of HCV-infected hepatocytes or the viremia levels and the histological activity index. In conclusion, we have shown that the HCV viremia reflects the extent of the infection in the liver and that the liver injury in chronic HCV infection is not directly related to either the number of infected hepatocytes or the serum HCV RNA concentration.     

Studies on TAQ1 polymorphism in the 3'untranslated region of IL-12P40 gene in HCV patients infected predominantly with genotype 3

Host immunity plays an important role in viral persistence and progression of liver disease in HCV infected patients. IL-12 induces production of IFN-gamma, a potent antiviral agent. IL-12 comprises two subunits; IL-p35 and IL-12p40, which are encoded by two different genes located on chromosome 3 and 5, respectively. Single nucleotide polymorphism at A1188C in the 3'UTR of IL-12p40 gene is associated with immune mediated diseases. Association of IL-12p40 A1188C polymorphism with the outcome of HCV infection was investigated in this study. Two hundred and fifty three histologically proven chronic hepatitis C patients (43 +/- 13 years, male:female: 185:68) and 380 matched controls were included. Genotyping was performed by RFLP and confirmed by direct sequencing. To assess correlation of immune gene polymorphism with severity of HCV-related liver disease, patients were divided into those with fibrosis score of < or = 2 (mild) or > 2 (severe), and histological activity index (HAI) of = 5 (mild) or > 5 (severe). The distribution of A/A, A/C or C/C alleles in the controls was comparable to the patients. The distribution of C/C allele was significantly more common in patients with mild as compared to severe fibrosis (23.7% vs. 6.25%, P = 0.004). No significant difference was observed for any of the genetic markers with HAI or with normal or raised alanine aminotransferase (ALT). These results show that the C/C allele of IL-12p40 gene could render genetic protection against development of severe liver disease in patients infected with HCV.