HCV-RNA Titer Research Articles

Expression of transforming growth factor beta-1 in chronic hepatitis and hepatocellular carcinoma associated with hepatitis C virus infection.

BackgroundTransforming growth factor beta-1 (TGFβ 1) has been suggested to play a role in the development, growth or progression of hepatocellular carcinoma (HCC). Genotype and serum titer of HCV also affect the occurrence of HCC in chronic hepatitis C. In this study, we were to evaluate the effects of genotype or serum titer of HCV on the expression of TGFβ 1. We also intended to examine the correlation between the up-regulation of TGFβ 1 and the association with HCC in patients with chronic hepatitis C.MethodsWe studied 19 patients with chronic hepatitis C and 18 with HCC associated with HCV infection. HCV genotype was determined by line probe reverse hybridization assay and the amount of HCV-RNA was quantitated by branched DNA signal amplification assay. Serum TGFβ 1 level was measured by enzyme linked immunosorbent assay.ResultsHCV genotypes of patients with HCC were similar to those without it. Serum HCV-RNA titer was higher in genotype 1b than in non-1b (p<0.05). Serum TGFβ 1 levels were higher in HCC than in chronic hepatitis (p<0.05). However, there was no significant difference in the serum TGFβ 1 level between genotype 1b and non-1b. Also, it was not correlated with the serum HCV-RNA titer or alanine aminotransferase levels.ConclusionTGFβ 1 seems to be overexpressed in HCC compared to that of chronic hepatitis C; it was not affected by serum ALT levels, genotype or serum HCV titer. It is suggested that TGFβ 1 may be associated with the malignant transformation of hepatocyte or the progression of HCV-associated HCC.

Treatment of chronic hepatitis C in patients who failed interferon monotherapy: effects of higher doses of interferon and ribavirin combination therapy

OBJECTIVE: The present study was designed to evaluate the effectiveness of interferon–ribavirin combination therapy for treatment of chronic hepatitis C virus (HCV) in patients who failed previous treatment with interferon monotherapy. METHODS: A total of 140 patients with well-documented chronic HCV who failed to achieve a virological (if HCV-RNA was assessed) or biochemical response (if HCV-RNA was not assessed) to interferon monotherapy, 3 mU three times weekly (TIW) for 3–18 months, were randomly assigned to one of three treatment groups. Group A patients were treated with 5 mU interferon TIW for 6 months. Ribavirin (1000–1200 mg daily) was added in those patients HCV-RNA positive at month 3. Group B patients were treated with 3 mU interferon TIW plus ribavirin (1000–1200 mg daily) for 6 months. The dose of interferon was increased to 5 mU TIW in those patients HCV-RNA positive at month 3. Group C patients were treated with 5 mU interferon TIW plus ribavirin (1000–1200 mg daily) for 6 months. Serum ALT and HCV-RNA were monitored during and after treatment for a total of 15 months. RESULTS: Seventeen percent of patients in group A became HCV-RNA negative by treatment month 3. Adding ribavirin resulted in one additional patient becoming HCV-RNA negative. However, none of the patients in this group achieved sustained virological response. Twenty-six percent of patients in group B became HCV-RNA negative by treatment month 3. Increasing the dose of interferon from 3 to 5 mU TIW increased virological response to 30%. However, sustained virological response was observed in only 14%. Thirty percent of patients in group C became HCV-RNA negative, but sustained virological response was observed in only 12%. Sustained virological response was found to be significantly greater in patients with a nontype 1 HCV genotype ( p < 0.002) and in patients who had a decline in HCV-RNA titer to a value <100,000 copies/ml during their previous course of interferon monotherapy ( p < 0.0001). None of the 12 sustained responders were African Americans ( p < 0.013). CONCLUSIONS: Retreatment of nonresponders with interferon–ribavirin combination therapy results in limited benefit; only 13% of patients achieved sustained virological response. Response was extremely poor in African Americans and those with HCV genotype 1.

Population pharmacokinetic and pharmacodynamic analysis of ribavirin in patients with chronic hepatitis C.

The population pharmacokinetics of ribavirin were assessed in patients with chronic hepatitis C virus (HCV) infection treated with interferon alpha-2b and ribavirin in four clinical efficacy studies. The authors collected 3450 ribavirin serum concentrations from 1105 patients at different treatment weeks for inclusion in the analysis. Population factors included gender, age, body weight, serum creatinine, creatinine clearance, and previous interferon treatment history. Ribavirin apparent clearance (CL/F) was calculated from individual patients' daily doses divided by concentration values, and the influence of these factors was assessed by multiple regression. Body weight, gender, age, and serum creatinine affected CL/F. Population mean CL/F estimates were 17.9 L/h (female) and 21.5 L/h (male) assuming an age of 40 years and body weight of 70 kg. Ribavirin apparent clearance increased as a function of body weight and decreased at ages greater than 40 years. Serum creatinine had little influence on CL/F, which may reflect the relatively normal renal function of these patients. Total CL/F variability was approximately 28%. The four covariates in the model explained 27% of this variability, and were thus of limited clinical significance because of the substantial residual variability not accounted for by the model. In assessing the relationship between pharmacokinetics and pharmacodynamics, the week 4 hemoglobin nadir value was negatively associated with week 4 ribavirin concentrations. The percentage of reduction from baseline was positively associated with ribavirin concentrations, although these data were highly variable. Loss of HCV-RNA at 24 weeks after completion of treatment was considered a response to interferon and ribavirin treatment in a logistic regression analysis of clinical and pharmacokinetic variables and treatment response in the interferon-naive patients. Hepatitis C virus genotype, pretreatment HCV-RNA titer, duration of treatment period, week 4 ribavirin concentration, and patient age affected the likelihood of response. Higher ribavirin concentrations at treatment week 4 were associated with a higher response rate. Variables that have predictive value for treatment outcome in patients treated with interferon and ribavirin are similar to those previously reported for interferon monotherapy.

Clinical, virological and histopathological features: long‐term follow‐up in patients with chronic hepatitis C co‐infected with S. mansoni

Infection with Schistosoma mansoni is endemic in Egypt leading to hepatic schistosomiasis and eventually portal hypertension. The prevalence of antibodies against hepatitis virus C among Egyptians is 14-51%. The aim of the present study was to investigate the influence of schistosomiasis on chronic hepatitis C with respect to the natural course of the disease, immunology, virology and histology. One hundred and twenty-six Egyptian patients classified into three groups: group A: chronic hepatitis C (n=33); group B: chronic schistosomiasis (n=30) and group C: chronic hepatitis C and chronic schistosomiasis (n=63) were enrolled and prospectively followed for 62.7 +/- 22 months. Patients infected with other hepatic viruses and/or parasites were excluded. Detailed history, clinical examination, CD4+ and CD8+ lymphocyte counts in blood, hematological and blood chemical values, abdominal ultrasonography, upper endoscopy, HCV RNA titer by RT/PCR, genotype and histological activity index in the liver biopsy were determined. Thirty patients (48%) with HCV and schistosomiasis had liver cirrhosis and Child-Pugh class C vs. five (15%) in HCV patients and none in the schistosomal group. HCV RNA levels ranged between 0.07 and 13 x 10(5) copies/ml in group A, and between 1 and 25 x 10(5) copies/ml in group C. HCV genotype 4 was detected in 58 patients with co-infection (92%) and 21 patients with HCV alone (64%). Patients with coinfection showed higher grading and staging scores in their liver biopsies. Hepatocellular carcinoma was detected only in patients with coinfection. During follow-up, the mortality rate was 12%, 3% and 48% in group A, B and C, respectively. Patients with concomitant HCV and schistosomiasis infection were characterized by more advanced liver disease, higher HCV RNA titers, predominance of HCV genotype 4, higher histologic activity, higher incidence of cirrhosis and hepatocellular carcinoma as well as a much higher mortality rate.

Clinical significance of IL-10 and TNF-A promoter polymorphisms in chronic hepatitis C (HCV) infection

INTRODUCTION: Elevated IL-IO or TNF-a in chronic HCV pts appears to contribute to viral persistence and play a role in resistance to IFNtherapy. Three biallelic polymorphisms in the IL-IO promoter and one in the TNF-a promoter (-308) appear to influence the production of ILIOand TNF-a, respectively. The functional effects of other polymorphisms in the TNF-a promoter has not been established. AIM: Identify polymorphisms in the IL-IO and TNF-a promoter regions of pts with chronic HCV and investigate significance of these polymorphisms in disease outcome and response to InterferonlRiba virin therapy. METHOD : 33 INFlRib treated chronic HCV pts ( 8 sustained responders and 15 non-responders) and 37 racially matched healthy individuals were selected for this study. All HCV pts received a minimum of 6 months of therapy. DNA extraction was followed by PCR amplification of segments extending from positions 1201 to 52I and 547 to +17 within the IL-10 and TNF-a promoters, respectively. Direct sequencing of purified amplification products was performed using the ABI 377 DNA Sequencer. RESULT : HCV pts and controls had a similar distribution of alleles at all known polymorphic sites with the exception of position -1082 of the IL-IO promoter. HCV pts were more likely to be (GIG) homozygous, while controls were more likely to have either the (NA) or (NG) genotype (p=0.07). No association was found between IL-IO (-1082, -819, -652. and -592) or TNF-a (-376, -308, -238, and -163) promoter polymorphisms and ALT, HCV RNA titer, genotype, liver histology or response to INFlRib therapy. Multivariate analysis revealed HCV genotype as the only predictor of a sustained response, and pretreatment HCV RNA titer as predictive of HCV RNA clearance 3 months after initiation of therapy but not sustained response. Two potentially novel polymorphic sites were identified at position -851(A->G) of the IL-IO promoter in 3nO (4%) pts and at position -49 (G->A) of the TNF-a promoter in Ino (1.4%) pts. CONCL USION: I) A polymorphism of the IL-10 promoter, which has been associated with high IL-10 production, is more commonly found in HCV pts than in controls. 2) The role of IL-10 and TNF-a promoter polymorphisms in disease progression and INFlRib therapy remains unclear. 3) Two novel polymorphisms were identified in the IL-IO and TNF-a promoter, but their functional significance has yet to be determined.

Chronic hepatitis C infection in patients with end stage renal disease: characterization of liver histology and viral load in patients awaiting renal transplantation

OBJECTIVES: Hepatitis C virus (HCV) is common in patients with end stage renal disease (ESRD) awaiting renal transplantation (RT). However, few data are available on the liver histology and viral titer in these patients relative to patients with HCV and normal renal function. The aims of this study were to assess liver histology, quantitative HCV-RNA titer, and alanine aminotransferase (ALT) levels in patients with ESRD awaiting RT, and to identify clinical predictors of histological progression to advanced bridging fibrosis and/or cirrhosis. METHODS: A total of 50 consecutive patients (mean age 42 yr, 62% male) with ESRD and HCV, who were awaiting RT, underwent liver biopsy. Two HCV populations, one with persistently normal ALT and another with elevated ALT, both with normal renal function, served as controls. HCV-RNA titer was assessed by quantitative PCR. RESULTS: Of the patients with ESRD, 94% had normal ALT. Log HCV RNA titer was significantly higher in patients with ESRD (5.8 ± 0.3) than in either normal ALT (5.4 ± 0.1) or elevated ALT (5.3 ± 0.1) controls ( p < 0.05). Knodell Histological Activity Index (HAI) in patients with ESRD was similar to that observed in control patients with normal ALT (4.8 ± 0.4 vs 4.9 ± 0.4) but significantly less ( p < 0.05) than that observed in control patients with elevated ALT (8.4 ± 0.5). The percentage of patients with bridging fibrosis or cirrhosis was similar in patients with ESRD and controls with persistently normal ALT (22% vs 13%) but significantly less ( p < 0.001) than that observed in control patients with elevated ALT (48%). No significant differences in ALT, HCV-RNA titer, duration on hemodialysis, or time from first possible exposure was observed between ESRD patients with advance fibrosis (n = 11) and those with mild disease (n = 39). CONCLUSIONS: Our data suggest that liver biopsy is necessary to exclude significant liver pathology in patients with HCV and ESRD, and to help define those patients in whom interferon treatment might be helpful.

Chronic hepatitis C infection in patients with end stage renal disease: characterization of liver histology and viral load in patients awaiting renal transplantation.

Hepatitis C virus (HCV) is common in patients with end stage renal disease (ESRD) awaiting renal transplantation (RT). However, few data are available on the liver histology and viral titer in these patients relative to patients with HCV and normal renal function. The aims of this study were to assess liver histology, quantitative HCV-RNA titer, and alanine aminotransferase (ALT) levels in patients with ESRD awaiting RT, and to identify clinical predictors of histological progression to advanced bridging fibrosis and/or cirrhosis. A total of 50 consecutive patients (mean age 42 yr, 62% male) with ESRD and HCV, who were awaiting RT, underwent liver biopsy. Two HCV populations, one with persistently normal ALT and another with elevated ALT, both with normal renal function, served as controls. HCV-RNA titer was assessed by quantitative PCR. Of the patients with ESRD, 94% had normal ALT. Log HCV RNA titer was significantly higher in patients with ESRD (5.8+/-0.3) than in either normal ALT (5.4+/-0.1) or elevated ALT (5.3+/-0.1) controls (p < 0.05). Knodell Histological Activity Index (HAI) in patients with ESRD was similar to that observed in control patients with normal ALT (4.8+/-0.4 vs 4.9+/-0.4) but significantly less (p < 0.05) than that observed in control patients with elevated ALT (8.4+/-0.5). The percentage of patients with bridging fibrosis or cirrhosis was similar in patients with ESRD and controls with persistently normal ALT (22% vs 13%) but significantly less (p < 0.001) than that observed in control patients with elevated ALT (48%). No significant differences in ALT, HCV-RNA titer, duration on hemodialysis, or time from first possible exposure was observed between ESRD patients with advance fibrosis (n = 11) and those with mild disease (n = 39). Our data suggest that liver biopsy is necessary to exclude significant liver pathology in patients with HCV and ESRD, and to help define those patients in whom interferon treatment might be helpful.

A randomized, controlled trial of maintenance interferon therapy for patients with chronic hepatitis C virus and persistent viremia

Background & Aims: At least half of patients with chronic hepatitis C virus (HCV) fail to respond to interferon or interferon/ribavirin therapy. Histological improvement is observed in some nonresponders. We conducted a randomized, controlled trial to determine if maintenance interferon therapy could prevent histological progression in this subset of nonresponders. Methods: Fifty-three patients with chronic HCV were enrolled. All were HCV-RNA positive after 6 months of treatment with interferon alfa-2b but had a histological response. Twenty-seven of the patients were randomly assigned to continue interferon (3 MU 3 times weekly) for 24 months; 26 patients discontinued treatment and were observed prospectively. Alanine aminotransferase (ALT) level and HCV-RNA titer were monitored, and liver biopsy was repeated every 12 months. Results: Before interferon therapy, the 2 groups were well matched for all demographic factors, serum ALT (94.0 ± 15.6), log HCV-RNA titer (5.85 ± 0.15 copies/mL), histology score (9.5 ± 0.2), and percentage with cirrhosis (25%). After 6 months of treatment, significant reductions ( P < 0.05) in serum ALT level (62.6 ± 9.6), log HCV-RNA titer (4.79 ± 0.13 copies/mL), and hepatic inflammation (4.0 ± 0.2) were observed. These improvements were maintained in the patients randomized to continue interferon. Stopping treatment was associated with an increase in serum ALT, log HCV-RNA, and hepatic inflammation back to baseline. After 30 months of treatment, mean fibrosis score declined from 2.5 to 1.7 and 80% of patients had histological improvement ( P < 0.03). Discontinuation of interferon was associated with an increase in mean fibrosis score from 2.2 to 2.4 and worsening of hepatic histology in 30% of patients ( P < 0.01). Conclusions: These data support the hypothesis that maintenance interferon may prevent histological progression of chronic HCV in patients who remain viremic. GASTROENTEROLOGY 1999;117:1164-1172

Natural history of hepatitis C in HIV-negative patients with congenital coagulation disorders

Background/Aims: Knowledge of the natural history of hepatitis C is useful for counselling patients and planning treatment. More data are needed from unselected patient groups without concomitant disease. The aim of this study was to describe the natural history of hepatitis C, two decades after infection, in a homogeneous and well-defined group of HIV-negative patients with congenital coagulation defects who had not received specific therapy for chronic hepatitis C. Methods: Medical history, physical examination, laboratory tests and abdominal ultrasonography were performed in 45 HCV-RNA positive, HIV-negative patients, mainly haemophiliacs, from a single centre. Patients were classified according to results of ultrasonography. Results: Two patients had experienced an episode of variceal bleeding; all others were asymptomatic. None had ascites. HCV-RNA titres were >500 000 copies/ml in 23 patients, genotype was 1 in 31 patients. Forty (89%) had elevated transaminases, liver synthesis function was diminished in 7 (16%), and platelet count in 8 (18%). Ultrasonography was normal in 26 (58%) patients, 12 (27%) had isolated splenomegaly, and 7 (16%) had liver nodularity compatible with cirrhosis. Univariate analysis disclosed higher transaminases and γGT, higher age at acquisition of infection and higher present age as risk factors for more advanced disease. Of these, only higher present age was an independent predictor in multivariate analysis. Conclusions: Median 19 years after infection, 58% of patients had no other signs of liver disease than raised transaminases, 16% had cirrhosis on ultrasonography. Only 2/45 patients had symptomatic disease. Higher present age is the main risk factor for advanced disease in this group.

Is hepatitis G/GB virus-C virus hepatotropic? Detection of hepatitis G/GB virus-C viral RNA in liver and serum

The recently identified hepatitis G virus (HGV, also named GB virus-C, GBV-C) appears to have similarities to hepatitis C virus and other flaviviridae. To better understand its clinical significance and hepatotropism, we collected liver tissue and matched serum samples from 56 patients undergoing liver transplantation. HGV/GBV-C RNA was detected by reverse transcription-nested PCR, using primers from the relatively conserved 5' noncoding region of the genome to detect HGV/GBV-C RNA and the amount was semiquantitatively estimated by serial 10-fold endpoint dilution. The presence and amount of HCV RNA was estimated by the same methodology. Seventeen patients (30%) had HGV/GBV-C RNA detectable either in liver or in serum, including two of three with cryptogenic liver disease. Interestingly, 5 of 17 (29%) patients had HGV/GBV-C RNA in serum but not liver, even with repeated testing of hepatic RNA from different portions of the liver. Furthermore, the titer of HGV/GBV-C RNA was significantly lower in liver than in serum in most samples (mean log titer, 1.33 vs. 2.56, P < 0.05). In contrast, all 21 patients with HCV RNA in serum also had the virus detectable in liver. In five patients coinfected with HCV and HGV/GBV-C, the mean titer of HCV RNA in liver was higher than that in serum (log titer, 2.8 vs. 3.0, P > 0.05). Thus, our results suggest that HGV/GBV-C is probably not hepatotropic and may replicate predominantly in sites other than the liver. These findings brings into question the role of HGV in causing significant liver disease.

Relationship between the effect of interferon therapy and the change of hepatitis C virus non-structural 5B gene.

Hepatitis C virus (HCV)-RNA titre has been regarded as a factor affecting the response to interferon (IFN) therapy of patients with chronic hepatitis C (CHC). The focus of our study is the investigation of the nucleotide sequence of HCV-RNA NS5B, which may code RNA-dependent RNA polymerase and NS5A in the sera of 33 patients with CHC prior to IFN therapy. Hepatitis C virus genotype and HCV-RNA titre were examined by polymerase chain reaction (PCR) and competitive reverse transcriptase-PCR. The sequence for HCV-RNA NS5B (nt 8331-8600 in 1b and 8410-8679 in 2a) was determined by direct sequencing. The changes of the predicted amino acids in the genotype-specific sites of HCV-J, HCV-BK, HC-J4/83, HCV-JT, HCV-N, HC-J6 and HCV-K2a were examined, and the mutation was defined when changes of amino acids in sites specific to different reported genotypes were revealed. The mutations were observed in 6/19 (32%) in genotype 1b and 9/14 (64%) in 2a. In the 1b group, complete response (CR) was achieved in 5/6 of the mutant and in 2/13 of the wild type groups (P < 0.05). No relationship was observed between IFN effectiveness and HCV-RNA titre in the 1b wild type group. In the 2a group, CR was achieved in 4/9 of the mutant and in 4/5 of the wild type groups. An inverse relationship between IFN responsiveness and HCV-RNA titre was apparent in 1b mutant, 2a wild and 2a mutant. These data suggest the possible relationship between changes in the HCV-NS5B gene and the effect of IFN therapy in CHC patients with genotype 1b.

Clinical significance of portal lymphoid aggregates/follicles in Chinese patients with chronic hepatitis C

OBJECTIVE: Portal lymphoid aggregates/follicles (lymphoid A/F) is a characteristically histological finding in patients with chronic hepatitis C. We assessed the prevalence of lymphoid A/F in Chinese patients with chronic hepatitis C and evaluated the correlation of this phenomenon with clinical, biochemical, immunological, virological, and other histological features of these patients. METHODS: Eighty-nine Chinese patients with chronic hepatitis C were enrolled and portal lymphoid A/F was evaluated in liver biopsy. Clinical, biochemical, immunological, histological, and virological data, including serum HCV RNA titer and HCV genotype and the response to interferon therapy, were compared between patients with and without portal lymphoid A/F. RESULTS: Twenty-nine (33%) of 89 patients with chronic hepatitis C had portal lymphoid A/F. Patients with lymphoid A/F had a significantly higher frequency of HCV genotype 1b infection ( p = 0.039) and had a significantly higher mean score of bile duct damage, periportal necroinflammation, and portal inflammation in liver histologies when compared with patients without lymphoid A/F. No significant difference in sex distribution, mean age, history of blood transfusion, serum liver biochemistry, presence of serum autoantibodies/cryoglobulinemia, serum viral titer, and response to interferon therapy was noted between the two groups. Multivariate logistic regression analysis showed HCV genotype 1b infection and periportal necroinflammation were significant independent predictors associated with portal lymphoid A/F. CONCLUSIONS: The presence of portal lymphoid A/F in Chinese patients with chronic hepatitis C was significantly correlated with HCV genotype 1b infection and periportal necroinflammation.

Clinical significance of portal lymphoid aggregates/follicles in Chinese patients with chronic hepatitis C.

Portal lymphoid aggregates/follicles (lymphoid A/F) is a characteristically histological finding in patients with chronic hepatitis C. We assessed the prevalence of lymphoid A/F in Chinese patients with chronic hepatitis C and evaluated the correlation of this phenomenon with clinical, biochemical, immunological, virological, and other histological features of these patients. Eighty-nine Chinese patients with chronic hepatitis C were enrolled and portal lymphoid A/F was evaluated in liver biopsy. Clinical, biochemical, immunological, histological, and virological data, including serum HCV RNA titer and HCV genotype and the response to interferon therapy, were compared between patients with and without portal lymphoid A/F. Twenty-nine (33%) of 89 patients with chronic hepatitis C had portal lymphoid A/F. Patients with lymphoid A/F had a significantly higher frequency of HCV genotype 1b infection (p = 0.039) and had a significantly higher mean score of bile duct damage, periportal necroinflammation, and portal inflammation in liver histologies when compared with patients without lymphoid A/F. No significant difference in sex distribution, mean age, history of blood transfusion, serum liver biochemistry, presence of serum autoantibodies/cryoglobulinemia, serum viral titer, and response to interferon therapy was noted between the two groups. Multivariate logistic regression analysis showed HCV genotype 1b infection and periportal necroinflammation were significant independent predictors associated with portal lymphoid A/F. The presence of portal lymphoid A/F in Chinese patients with chronic hepatitis C was significantly correlated with HCV genotype 1b infection and periportal necroinflammation.

Detection of genomic- and minus-strand of hepatitis C virus RNA in the liver of chronic hepatitis C patients by strand-specific semiquantitative reverse-transcriptase polymerase chain reaction.

Studies aimed at correlating the intrahepatic hepatitis C virus (HCV)-RNA level and anatomo-clinical features have been difficult because of sensitivity and specificity shortcomings of available techniques. We titered the genomic- and minus-strand HCV RNAs by a strand-specific, semiquantitative, genotype-independent reverse-transcriptase polymerase chain reaction (RT-PCR) in the liver tissue of 61 patients with chronic hepatitis C. Findings were correlated with the levels of HCV RNA in the serum, the HCV genotype, the expression of intrahepatic HCV antigens, the histological activity (using separate scores for the lobular and the portal/periportal necroinflammatory activity and for the fibrosis), and the response to interferon alfa (IFN-alpha) treatment. Genomic- and minus-strand HCV RNA were detected in 59 and 57 liver specimens, respectively. The HCV-RNA level in the serum correlated with the genomic-strand, but not with the minus-strand, HCV-RNA titer in the liver. No correlations were found between either strand of the intrahepatic HCV RNA and the level of expression of HCV antigens in the liver, or with the grading/staging of the underlying liver disease. The response to IFN-alpha treatment could be predicted by the serum HCV-RNA level and genotype, but not by the intrahepatic level of genomic- or minus-strand HCV RNA. These results suggest that, although the detection of the minus-strand HCV RNA reliably identifies the presence of replicating HCV in its target organ, the quantitative measurement of viremia remains the clinically meaningful "golden standard" for assessing the level of HCV replication.

Interferon-α-2B and ribavirin in combination for chronic hepatitis C patients not responding to interferon-α alone: an italian multicenter, randomized, controlled, clinical study

Objective: The aim of the study was to assess the efficacy of interferon (IFN)-α-2b and ribavirin in combination in the treatment of chronic hepatitis C (CHC) patients unresponsive to a previous treatment with IFN-α-2b alone. Methods: We conducted a randomized study in 303 CHC patients. One hundred fifty-two patients received subcutaneous administration of recombinant IFN-α-2b (3 MU thrice weekly) and ribavirin (1000–1200 mg/daily per os), whereas 151 received IFN-α-2b alone (6 MU thrice weekly). Both ribavirin and IFN-α-2b were given for 24 wk, regardless of treatment response. Alanine aminotransferase (ALT) levels and HCV RNA titer were checked during the treatment period and for a further 24 wk. Results: Normal ALT levels were observed in 64.5% of the patients treated with IFN-α and ribavirin and in 22.6% of the patients treated with IFN-α alone. In the group of patients receiving IFN-α and ribavirin HCV RNA was not detectable in 40% of patients responders and remained undetectable in 44.2% of sustained responders. In the group of patients receiving IFN-α alone HCV RNA was not detectable in 24.2% of patients responders and remained not detectable in 33.3% of sustained responders. Conclusions: A 24-wk treatment course with IFN-α and ribavirin given to patients with a previous lack of response to IFN-α alone offers a chance of a sustained biochemical and virological response, at least in a subset of such patients. The role of long-term therapy in inducing prolonged remission still remains to be explored.

A long-term follow-up study on risk factors for hepatocellular carcinoma among Japanese patients with liver cirrhosis.

To identify virological parameters (serostatus of hepatitis B surface antigen [HBsAg] and antibodies to hepatitis C virus [anti‐HCV], HCV genotypes and HCV‐RNA titer) and other clinico‐biological and lifestyle variables that may influence or predict the development of hepatocellular carcinoma (HCC) in cirrhosis, we followed 100 cirrhotic patients without HCC, who visited Kyushu University Hospital between 1985 and 1987, until the end of 1995 (follow‐up rate: 98%; average follow‐up period: 5.3 years). After elimination of 4 patients who developed HCC or were censored within the initial 6 months, 37 (39%) out of 96 patients developed HCC during follow‐up. As compared with HBsAg(+) patients, anti‐HCV(+) HBsAg(–) patients demonstrated significantly elevated HCC risk (adjusted hazard ratio [HR]=5.85, 95% confidence interval [CI] 1.65–20.67). Genotype 1 HCV infection was not associated with increased risk compared with genotype 2 (HR = 0.64, 95% CI 0.21–1.99). For genotype 1 HCV infection, patients with HCV‐RNA levels <1 Meq/ml tended to present lower risk than patients with ≥1 Meq/ml (P= 0.03). Male sex, advanced Child's class, lower serum albumin, and higher serum aminotransferase and α‐fetoprotein were also found to be strong predictors. Overall, drinking and smoking habits were not associated with significantly elevated risk. Among virological parameters, anti‐HCV positivity and, possibly high HCV‐RNA titer, were predictive of HCC occurrence in cirrhosis in our clinical setting.

Hepatitis C virus (HCV) hypervariable region 1 complexity does not correlate with severity of liver disease, HCV type, viral load or duration of infection

Backgroud/Aims: Several studies have suggested that infection with a highly heterogeneous population of hepatitis C virus correlates with a low response rate to interferon. It is still debated, however, whether or not this heterogeneity might be associated with liver disease severity. The aim of this study was to analyse hepatitis C virus genome complexity in patients with various stages of liver disease. Methods: We used polymerase chain reaction-single strand conformation polymorphism (SSCP) analysis to estimate the degree of complexity of the hypervariable region (HVR1) in 95 anti-HCV and serum HCV-RNA positive patients. They were divided into two groups according to Knodell's histological activity index (HAI) grading: 22 with HAI <4 and 73 with HAI > -4, including 19 with cirrhosis. Results: The number of visible SSCP bands ranged from 1 to 7. There was no significant difference in the number of SSCP bands between patients with HAI <4 and patients with HAI > -4 (median number of bands was 4 in both groups). The number of SSCP bands was not correlated to the biochemical activity, the genotype, the HCV-RNA titre or the duration of hepatitis C virus infection. Conclusions: The HCV-HVR1 complexity profile alone does not correlate with the severity of liver disease, whatever, the biological and virological profile of the viral infection.

Serum levels of soluble Fas antigen in chronic hepatitis C patients

BAckground/Aims: In chronic hepatitis C, the expression of Fas antigen on hepatocytes is upregulated and Fas ligand expression is detected on liver-infiltrating mononuclear cells. Thus Fas antigen/Fas ligand-mediated apoptosis is thought be involved in hepatic injury in chronic hepatitis C. The soluble form of Fas antigen has been detected in serum and shown to inhibit Fas-mediated apoptosis. The present study was done to evaluate the relationship of serum soluble Fas antigen levels with disease activity. Methods: Serum soluble Fas antigen levels were measured by enzyme-linked immunosorbent assay for 68 chronic hepatitis C patients and compared with those in normal volunteers, chronic hepatitis B patients and autoimmune hepatitis patients. These levels were compared with histological activity, ALT leves, HCV-RNA titer and Fas expression on hepatocytes. Results: Serum soluble Fas antigen levels in chronic hepatitis C patients (3.24±1.55 ng/ml) were significantly higher than those in normal volunteers (1.70±1.01 ng/ml) ( p<0.01). They showed no difference from those in chronic hepatitis B or autoimmune hepatitis patients. Histologically, soluble Fas antigen levels showed correlation with the levels of liver inflammation ( p<0.01). However, no relationship was observed between serum soluble Fas antigen and serum ALT levels or HCV-RNA titer. Serum soluble Fas antigen levels showed correlation with the levels of Fas antigen expression in liver tissue ( p<0.05). Conclusions: These findings suggest that serum soluble Fas antigen may reflect the expression levels of Fas antigen on hepatocytes and the severity of liver inflammation in chronic hepatitis C.

Predictors of patient and graft survival following liver transplantation for hepatitis C.

End-stage liver disease secondary to hepatitis C virus (HCV) infection is the leading indication for liver transplantation in the United States. Recurrence of HCV infection is nearly universal. We studied the patients enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database to determine whether pretransplantation patient or donor variables could identify a subset of HCV-infected recipients with poor patient survival. Between April 15, 1990, and June 30, 1994, 166 HCV-infected and 509 HCV-negative patients underwent liver transplantation at the participating institutions. Median follow-up was 5.0 years for HCV-infected and 5.2 years for HCV-negative recipients. Pretransplantation donor and recipient characteristics, and patient and graft survival, were prospectively collected and compared. Cumulative patient survival for HCV-infected recipients was similar to that of recipients transplanted for chronic non-B-C hepatitis, or alcoholic and metabolic liver disease, better than that of patients transplanted for malignancy or hepatitis B (P = .02 and P = .003, respectively), and significantly worse than that of patients transplanted for cholestatic liver disease (P = .001). Recipients who had a pretransplantation HCV-RNA titer of > or = 1 x 10(6) vEq/mL had a cumulative 5-year survival of 57% versus 84% for those with HCV-RNA titers of < 1 x 10(6) vEq/mL (P = .0001). Patient and graft survival did not vary with recipient gender, HCV genotype, or induction immunosuppression regimen among the HCV-infected recipients. While long-term patient and graft survival following liver transplantation for end-stage liver disease secondary to HCV are generally comparable with that of most other indications, higher pretransplantation HCV-RNA titers are strongly associated with poor survival among HCV-infected recipients.

Retrospective study on the impact of hepatitis C virus infection on kidney transplant patients over 20 years.

The majority of chronic hepatitis is ascribable to hepatitis C virus (HCV) infection, whereas the clinical impact has not been understood in kidney transplant recipients. Our current study was carried out to assess the impact of HCV infection on kidney recipients over the long-term, and to investigate the effect and risk of interferon-alpha (IFN-alpha) therapy for chronic active hepatitis C. Hepatitis B surface antigen (HBsAg) and antibody to HCV (HCVAb) were examined prospectively and retrospectively in 280 patients, who underwent kidney transplants in the period from 1973 to 1996. The patient survival rate, the graft survival rate, the incidence of liver dysfunction and the cause of mortality among the HCV infected and noninfected groups were analyzed. IFN-alpha therapy was performed on 10 patients with chronic active hepatitis C. Prevalence of the hepatitis virus was quite high at 34.3% (96/280): the frequency of the HBsAg carrier was 3.2% (9/280), that of the HCVAb carrier was 28.6% (80/280) and that of the both carriers was 2.5% (7/280). The other 184 cases (65.7%) were negative for both HBsAg and HCVAb. Liver dysfunction developed at the significantly higher incidence of 55% in HCVAb carriers compared to the 9.2% of the noninfected group (P<0.01). HCVAb carriers had a poor survival rate in the second decade compared to the noninfected group: 83.7% vs. 88.91% for 10-year survival (P=0.44) and 63.9% vs. 87.9% for 20-year survival (P<0.05). The poor survival rate was a result of the mortality from liver disorder. Five patients died of such disease in the infected groups whereas no noninfected patient died in the same period (p<0.01). As the result of IFN-alpha therapy, biochemical activity normalized or improved in eight cases, whereas the HCV-RNA titer was reduced only in three patients. Only one patient maintained normal biochemical markers and undetectable levels of HCV-RNA for 2 years after treatment. The therapy was discontinued for five patients with the adverse effects of acute rejection, deterioration of diabetes, and depression. HCV infection has a significant impact on kidney transplant recipients over the long term and in particular affects them in the second decade. Our pilot study revealed only partial efficacy of IFN-alpha therapy for HCV-infected recipients, but with the high risk of acute rejection.