Anti-viral therapy can be delayed or avoided in a significant proportion of HBeAg-negative Caucasian patients in the Grey Zone.

BACKGROUND: Grey Zone (GZ) is an ill-defined situation including patients falling between inactive carrier (IC) state and HBeAg-negative chronic hepatitis B (HBeAg-negative CHB). AIMS: To assess the long-term outcomes of GZ patients compared to IC in the absence of treatment. METHODS: Retrospective analysis of 287 IC and GZ HBeAg-negative patients. Patients were classified into 4 groups at baseline: HBV-DNA <2000 IU/mL and ALT <40 U/L (IC), HBV-DNA <2000 IU/mL and ALT 40-80 U/L (GZ-1), HBV-DNA 2000-20 000 IU/mL and ALT <40 U/L (GZ-2) or ALT 40-80 U/L (GZ-3). Data were also analysed using AASLD ALT criteria. RESULTS: After a median follow-up of 8.2 (5-19) years, HBsAg loss occurred in about 15% ICs or GZ patients. Transition into IC state occurred in 40% of GZ patients. DNA fluctuations >2000 IU/mL correlated inversely with transition into IC and HBsAg loss. HBsAg levels were significantly lower in ICs than in GZ patients (338 IU/mL [20-3269] vs 5763 IU/mL [2172-17 754]; P < 0.05). Among the latter group, there was an increasing gradient of HBsAg levels from GZ-1 to GZ-3 patients (P < 0.05). HBeAg-negative CHB occurred in only 18 (6.3%) GZ patients. No patient developed cirrhosis nor advanced fibrosis. ALT/HBV-DNA fluctuations and HBeAg-negative CHB development were more frequent in genotype B/C patients, whereas HBsAg loss occurred only in genotype A/D patients. CONCLUSIONS: Most Caucasian GZ patients present excellent long-term outcomes in the absence of treatment, with a high rate of HBsAg loss and low rate of progression to HBeAg-negative CHB. HBV-genotyping and HBsAg levels could help to predict outcomes and better classify GZ patients.

Predicting the development of liver cirrhosis by simple modelling in patients with chronic hepatitis C.

BACKGROUND: Data are scarce on the natural history of chronic hepatitis C (CHC) in patients with mild hepatitis C who did not respond to anti-viral therapy. AIM: To predict the risk of progression to cirrhosis, identifying patients with the more urgent need for therapy with effective anti-virals. METHODS: A cohort of 1289 noncirrhotic CHC patients treated with interferon-based therapy between 1990 and 2004 in two referral hospitals were followed up for a median of 12 years. RESULTS: Overall, SVR was achieved in 46.6% of patients. Data from a randomly split sample (n = 832) was used to estimate a model to predict outcomes. Among nonresponders (n = 444), cirrhosis developed in 123 (28%) patients. In this group, the 3, 5 and 10-year cumulative probabilities of cirrhosis were 4%, 7% and 22%, respectively, compared to <1% in the SVR-group (P < 0.05). Baseline factors independently associated with progression to cirrhosis in nonresponders were: fibrosis ≥F2, age >40 years, AST >100 IU/L, GGT >40 IU/L. Three logistic regression models that combined these simple variables were highly accurate in predicting the individual risk of developing cirrhosis with areas under the receiving operating characteristic curves (AUC) at 5, 7 and 10 years of ~0.80. The reproducibility of the models in the validation cohort (n = 457, nonresponders = 244), was consistently high. CONCLUSIONS: Modelling based on simple laboratory and clinical data can accurately identify the individual risk of progression to cirrhosis in nonresponder patients with chronic hepatitis C, becoming a very helpful tool to prioritise the start of oral anti-viral therapy in clinical practice.

Increased serum hepcidin levels in patients with porphyria cutanea tarda.

BACKGROUND: Increased iron stores- are common in porphyria cutanea tarda (PCT) patients, but the pathophysiological pathways remain unknown. Down-regulation of hepcidin, a peptide which regulates systemic iron homeostasis, has been demonstrated in different conditions associated with PCT, such as haemochromatosis, chronic hepatitis C (CHC) and excessive alcohol intake. However, serum hepcidin levels have not yet been studied in PCT patients. OBJECTIVE: To measure the serum hepcidin levels in patients with PCT, CHC and control patients, and to assess the association of hepcidin with serum markers of inflammation, iron overload and oxidative stress. METHODS: Hepcidin levels were measured by a competitive enzyme-linked immunosorbent assay in serum samples of patients presenting PCT (n = 30), CHC (n = 31) and healthy volunteers (n = 52). RESULTS: The mean of serum hepcidin levels was significantly higher in the PCT group (129.6 ng/mL) in comparison with the mean values in the CHC (41.3 ng/mL) and control (70.8 ng/mL) groups. The serum concentration of ferritin and interleukin-6 (IL-6) was also significantly higher in the PCT group, and correlated strongly with the hepcidin levels. The PCT patients with hepatitis C virus (HCV) infection showed significantly higher hepcidin levels than the group of CHC patients without porphyria. CONCLUSION: Serum hepcidin levels are increased in patients with PCT suggesting that the mechanisms regulating iron homeostasis in PCT differ from those involved in other related disorders, such as haemochromatosis, HCV infection or alcohol abuse.

Donor and recipient IL28B polymorphisms in HCV-infected patients undergoing antiviral therapy before and after liver transplantation.

IL28B gene polymorphisms are associated with the response to antiviral therapy in hepatitis C patients. We investigated the influence of IL28B polymorphisms on the response to therapy before and after liver transplantation (LT). Genotyping of SNPs rs8099917 and rs12979860 was performed in 128 HCV-infected liver transplant recipients and in their donors; all patients underwent antiviral treatment after LT. The prevalence of genotypes rs12979860CC and rs8099917TT was higher in donors than in recipients (50% vs.19%, p < 0.001 and 67% vs. 38%, p < 0.001, respectively). Response to antiviral therapy was significantly higher for recipient genotype rs12979860CC as compared to rs12979860CT/TT both before (100% vs. 48% p = 0.013) and after LT (59% vs. 25% p = 0.002). The figures were almost identical for SNP rs8099917. Sustained virological response after LT was particularly high in patients with favorable recipient and donor genotypes (p < 0.01 for both SNPs). In a subgroup of 34 patients treated while awaiting LT, a favorable donor IL28B genotype was associated with an improved virological response after LT. Our results support a major role of recipient IL28B genotype in the response to antiviral treatment for hepatitis C recurrence. Interestingly, donor genotype also seems to influence the response pattern, especially in recipients who have a favorable IL28B genotype.

Assessment of liver fibrosis before and after antiviral therapy by different serum marker panels in patients with chronic hepatitis C.

BACKGROUND: Liver biopsy is the reference standard to assess liver fibrosis in chronic hepatitis C. AIM: To validate and compare the diagnostic performance of non-invasive tests for prediction of liver fibrosis severity and assessed changes in extracellular matrix markers after antiviral treatment. METHODS: The performances of Forns' score, AST to platelet ratio index (APRI), FIB-4 index and Enhanced Liver Fibrosis (ELF) score were validated in 340 patients who underwent antiviral therapy. These scores were determined 24 weeks after treatment in 161 patients. RESULTS: Forns' score, APRI, FIB-4 and ELF score showed comparable diagnostic accuracies for significant fibrosis [area under the receiver operating characteristic curve (AUROC) 0.83, 0.83, 0.85 and 0.81, respectively]. To identify cirrhosis, FIB-4 index showed a significantly better performance over APRI and ELF score (AUROC 0.89 vs. 0.83 and 0.82, respectively). ELF score decreased significantly in patients with sustained virological response (SVR) (P < 0.0001) but remained unchanged in nonresponders. Non-1 hepatitis C virus (HCV) genotype, baseline lower HCV RNA, glucose, hyaluronic acid and higher cholesterol levels were independently associated with SVR. CONCLUSIONS: Simple panel markers and ELF score are accurate at identifying significant fibrosis and cirrhosis in chronic hepatitis C. A decrease in ELF score after antiviral treatment reflects the impact of viral clearance in hepatic extracellular matrix and probably in the improvement of liver fibrosis.

Clinical trial: pharmacodynamics and pharmacokinetics of re-treatment with fixed-dose induction of peginterferon alpha-2a in hepatitis C virus genotype 1 true non-responder patients.

BACKGROUND: Patients infected with hepatitis C virus genotype 1 who are true non-responders to previous therapy suffer from a very difficult-to-cure disease. New approaches to treatment are necessary. AIM: To explore the efficacy, pharmacokinetics and safety of fixed-dose induction with peginterferon alpha-2a and ribavirin in this difficult-to-cure population. METHODS: Seventy-five hepatitis C virus genotype 1 true non-responder patients to a previous interferon-based combination regimen were randomised to receive peginterferon alpha-2a 360, 270 or 180 microg/week for 12 weeks, followed by 180 microg/week for 36 weeks, in combination with ribavirin (1000/1200 mg/day). Peginterferon alpha-2a concentration was measured throughout the study. RESULTS: Sustained virological response rates were 38%, 30% and 18%, in the 360, 270 and 180 microg/week groups, respectively (relapse rates: 25%, 50% and 64%, respectively). The area under the serum concentration-time curve of peginterferon alpha-2a from 0-12 weeks increased in a dose-dependent manner (P < 0.0001) and was associated with the sustained virological response (odds ratio: 1.35; 95% CI: 0.89, 2.06). The three regimens were equally well tolerated. CONCLUSION: Fixed-dose induction of peginterferon alpha-2a resulted in increased drug exposure and improved the likelihood of achieving a cure, without compromising safety in hepatitis C virus genotype 1 true non-responder patients.

Cryoglobulinaemia associated with hepatitis C virus: influence of HCV genotypes, HCV-RNA viraemia and HIV coinfection.

To determine whether the clinical and immunological expression of patients with cryoglobulinaemia associated with chronic hepatitis C virus (HCV) infection varied according to HCV-RNA load, HCV genotype or human immunodeficiency virus (HIV) coinfection. We studied 340 HCV patients (188 women and 152 men, with a mean age of 49 years) consecutively diagnosed with cryoglobulinaemia between 1993 and 2003 in our hospital. HCV infection was confirmed by serum HCV-RNA determination in all patients. Two hundred and forty-eight (73%) patients had asymptomatic cryoglobulinaemia and 92 (27%) presented cryoglobulinaemic symptoms. Patients with genotype 1 had a higher mean age at diagnosis of cryoglobulinaemia (48.2 vs 40.2 yrs, P < 0.001) and a higher prevalence of cryoglobulinaemic symptoms (25%vs 10%, P = 0.02), especially of vasculitic features (19%vs 5%, P = 0.014). In comparison with monoinfected HCV patients, those with HIV coinfection had a lower mean age at diagnosis of cryoglobulinaemia (40.4 vs 52.8 years, P < 0.001), a lower prevalence of cryoglobulinaemic symptoms (15%vs 34%, P < 0.001), vasculitis (10%vs 28%, P < 0.001), associated systemic autoimmune disease (3%vs 14%, P = 0.001), rheumatoid factor (30%vs 70%, P = 0.001) and hypocomplementaemia (50%vs 78%, P = 0.01). In HCV-HIV patients, a high viral load was associated with a high frequency of symptomatic cryoglobulinaemia, especially in patients with a high viral load of the two viruses (50%vs 7%, P = 0.001) A higher frequency of cryoglobulinaemic symptoms (especially vasculitis) was found in patients with HCV monoinfection and in those carrying HCV genotype 1. In contrast, patients with HIV coinfection presented a threefold lower prevalence of vasculitis. Associated HIV infection significantly attenuated the clinical and immunological expression of cryoglobulinaemia, except in coinfected patients with high viral loads for the two viruses.

Evolution of the NS3 and NS5B regions of the hepatitis C virus during disease recurrence after liver transplantation.

In patients with hepatitis C virus (HCV)-related cirrhosis, infection recurrence is universal after liver transplantation (LT). The relevance of host and virus-related factors on the outcome of hepatitis C recurrence is poorly understood. This study analyzed the relationship between the genetic evolution of the Non-Structural (NS)3 protease and NS5B polymerase regions of HCV and the severity of hepatitis C recurrence. Thirty-three patients were classified as having mild (n = 16) or severe recurrence (n = 17), according to the degree of fibrosis in liver biopsies obtained 1 year after transplantation. Viral load and consensus sequences of the NS3 and NS5B domains were determined in a pre-LT and in four post-LT sequential serum samples. At week 12 after LT, viremia was significantly higher in patients with severe recurrence. NS3 and NS5b regions evolved independently after LT. The genetic evolution of NS3 domain was not related to the severity of the recurrence. However, the diversification in the NS5B region later than 12 weeks after LT was greater in patients with mild than in those with severe recurrence, suggesting a stronger immune pressure in the first group. These observations highlight the complex interplay between viral evolution and clinical outcomes in the LT setting.

Pacientes naïve con genotipo 1 / Treatment-naive patients with genotype 1

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Sensitivity to antiviral therapy may change after liver transplantation in patients with chronic hepatitis C virus infection.

In hepatitis C virus (HCV)-infected patients, it is generally assumed that the pattern of response to antiviral therapy remains unaltered after liver transplantation (LT). However, changes in the circulating HCV quasispecies and in the gene expression profiles of the graft might influence response to treatment after LT. We evaluated 22 HCV-infected patients who received antiviral treatment while awaiting LT and in whom HCV infection recurred. Eleven of these patients underwent a new antiviral treatment course. Our study analyses the early virological response to both treatment courses to assess the influence of the changes in HCV on the response to therapy. Patients were considered early virological responders (EVR) if viral load declined > or = 2 log10 during the first 12 weeks of therapy. The remaining individuals were considered nonresponders (NR). HCV sequences from hypervariable region 1 and nonstructural 5A (NS5A) region before both treatment regimens were compared. Of 11 patients, 8 (73%) showed identical early response to both courses of therapy (group A: five EVR-EVR, three NR-NR). Interestingly, the response changed in three patients (27%) (group B): two NR became EVR after transplantation, whereas one EVR became NR. Fixation of mutations within the NS5A occurred preferentially in group B (100%) compared with group A (37%)(P = 0.12). However, the number of fixed mutations was not significantly different between groups, suggesting that the changes in sensitivity to therapy after LT are not exclusively dependent on variations in HCV strains. In conclusion, in HCV-infected patients undergoing LT, the pattern of response to antiviral treatment may change after transplantation, and this possibility needs to be incorporated in clinical practice.

Antimitochondrial antibodies in patients with chronic hepatitis C virus infection: description of 18 cases and review of the literature.

To describe the clinical and immunologic patterns of disease expression of patients with chronic hepatitis C virus (HCV) infection and positive antimitochondrial antibodies (AMA). We investigated the presence of AMA in 237 consecutive HCV patients with extrahepatic manifestations from an International Registry. AMA were detected by indirect immunofluorescence in triple rat tissue (liver, stomach and kidney), aceton-fixed criosections and FITC-conjugated rabbit anti-human immunoglobulins. We found positive AMA in 18 (8%) out of 237 HCV patients. All patients were female with a mean age at protocol inclusion of 65.8 years (ranging from 37 to 87 years). Twelve (67%) patients fulfilled classification criteria for systemic autoimmune diseases (SAD), including Sjögren's syndrome (n = 7), systemic sclerosis (n = 3) and systemic lupus erythematosus (n = 2). Fourteen (78%) of the HCV-AMA patients presented at least one of the highly suggestive characteristics of primary biliary cirrhosis (PBC): 9 (50%) had a specific M2 pattern, 6 (33%) had more than twice normal levels of alkaline phosphatase, 5 (28%) had raised IgM levels and 4 (22%) a histological pattern compatible with PBC. Five (28%) patients developed neoplasia after detection of AMA. Seven (39%) patients died, due to neoplasia (n = 4), cirrhotic complications (n = 2) and hepatopulmonary syndrome (n = 1). We describe a subset of HCV patients with positive AMA who presented a broad spectrum of clinical features, including liver, autoimmune and neoplasic manifestations. Two-thirds of these patients presented an associated SAD, mainly Sjögren's syndrome or systemic sclerosis, together with a high frequency of multiple autoantibodies and an increased prevalence of cirrhosis and neoplasia.

Consensus conference on chronic viral hepatitis and HIV infection: updated Spanish recommendations.

Chronic hepatitis B and C represent a leading cause of morbidity and mortality among human immunodeficiency virus (HIV)-infected patients worldwide. New treatment options against both hepatitis B (HBV) and C (HCV) viruses have prompted us to update previous recommendations for the management of coinfected individuals. Fifteen topics (nine related to HCV, five to HBV and one to both viruses) were selected for this purpose. A panel of Spanish experts in the field was invited to review these areas and propose specific recommendations, which were scored according to the Infectious Disease Society of America (IDSA) grading system. These guidelines represent a comprehensive and updated overview on the management of hepatitis B and C in HIV-infected patients.

Rationale and design of TeraViC-4 study: a phase III, randomized clinical trial to evaluate the effects of treatment duration with peginterferon alfa-2a (40-kDa) and ribavirin in naïve patients with chronic hepatitis C virus infection without early virological response at week 4.

Several studies are available on the efficacy and safety of 40 kDa branched peginterferon alfa-2a (40-kDa) combined with ribavirin in the treatment of chronic hepatitis C patients. The TeraViC-4 study is a phase III, randomized, parallel group, multicenter study that includes two additional open arms. The main objective is to investigate if extended therapy over 72 weeks increases the rate of sustained virological response induced by a standard 48-week treatment period in naïve patients with chronic hepatitis C who do not show an early virological response. All patients will be treated with peginterferon alfa-2a (40-kDa), 180 micrograms subcutaneous (s.c.) once-weekly, and ribavirin, 400 mg b.i.d. Virological response will be assessed by a hepatitis C virus ribonucleic acid (HCV-RNA) qualitative polymerase chain reaction (PCR) test. Non-early responders (HCV-RNA still detectable after 4 weeks of therapy) will be randomly separated to receive combination therapy for 44 or 68 additional weeks. Early responders (undetectable HCV-RNA at week 4) will be allocated into two open arms according to HCV genotype and basal viral load, and they will be treated for 20 or 44 additional weeks. All patients will be followed for 24 weeks on no therapy. A total of 504 patients are planned to be included in the study in order to reach the required sample size in the two randomized groups. Efficacy of treatment will be assessed by determination of HCV-RNA and the primary efficacy variable is the rate of sustained virological response (after 24 weeks of treatment-free follow-up) in patients without early virological response. Secondary efficacy variables are the rate of sustained biochemical response, the rate of response in function of HCV genotype, viral load and treatment duration. Safety data will also be recorded and analyzed.

Long-term follow-up of chronic hepatitis C in patients diagnosed at a tertiary-care center.

BACKGROUND/AIMS: The natural history of chronic hepatitis C (HCV) is not completely understood. This study was aimed to evaluate the long-term outcome of the disease over a prolonged period of time and to identify factors associated with progression. METHODS: One hundred and sixteen patients with non-cirrhotic chronic non-A, non-B hepatitis consecutively diagnosed at a tertiary hospital between 1971 and 1977 were followed until December 1998 or until death. Patients with significant alcohol intake were excluded from the study. Variables obtained at the time of diagnosis, including epidemiological, clinical, laboratory, and histological data were recorded to determine risk factors associated with the development of liver cirrhosis and hepatic decompensation. RESULTS: Based on complete follow-up data, the development of liver cirrhosis and hepatic decompensation was evaluated in 94 and 114 of the 116 patients, respectively. Thirty-seven (39.3%) of 94 patients developed liver cirrhosis; an aspartate aminotransferase (AST) value higher than 70 IU/L was associated with development of cirrhosis (odds ratio (OR) 4.22, 95% CI 1.3-13.8). Hepatic decompensation occurred in 12 (10.5%) of 114 patients, its cumulative probability being 2.8% at 10 years, 5.2% at 15 years and 19.8% at 20 years. The only factor independently associated to the development of hepatic decompensation was the presence of fibrosis (stage 2 or 3) in the initial liver biopsy (OR 4.1, IC 95% 1.22-13.9). Liver-related death occurred only in seven (6%) of 114 patients. In comparison with the 116 patients diagnosed in the 1970's, patients with chronic hepatitis C diagnosed in 1999 were younger, more often asymptomatic, had lower AST and alanine aminotransferase (ALT) values and had significantly lower grade and stage histological scores. CONCLUSIONS: In summary, chronic hepatitis C had a high rate of progression to liver cirrhosis over a prolonged follow-up. However, this might be related to the fact that two decades ago the diagnosis was made at a significantly more advanced stage of the disease. Patients at high risk of progression can be identified by biochemical and histological variables at the time of diagnosis.

Abrupt onset of diabetes during interferon-alpha therapy in patients with chronic hepatitis C.

INTRODUCTION: Interferon-alpha (IFN-alpha) is now widely used in the treatment of chronic hepatitis C. Few patients have been reported as developing impaired glucose tolerance or diabetes mellitus (DM) using this therapy. The explanation for the development of DM in chronic hepatitis C treated with IFN-alpha is unclear. We report two patients who developed an abrupt onset of diabetes during IFN-alpha for chronic hepatitis C. CASE REPORTS: Two male middle-aged patients were admitted to our hospital for an abrupt onset of diabetes, in diabetic ketoacidosis, with a very short duration of hyperglycaemic symptoms. Their clinical course was similar. Case 1 never demonstrated any markers of pancreatic immunogenicity. Case 2 had high levels of decarboxylase glutamic acid autoantibodies (GADAb), before the IFN-alpha treatment that persisted. We compared initial beta-cell function and metabolic control with a group of middle-aged patients from our hospital who had recently been diagnosed with Type 1 diabetes mellitus (DM1). In contrast to these, the onset of the disease was particularly severe with beta-cell function substantially impaired and displaying unstable short-term metabolic control. CONCLUSIONS: Type 1 diabetes should be considered as a potential complication if IFN is administered to patients with chronic hepatitis C. Its onset may be severe and result in short-term difficulties in metabolic control.

Influence of the dynamics of the hypervariable region 1 of hepatitis C virus (HCV) on the histological severity of HCV recurrence after liver transplantation.

Recurrence of hepatitis C virus (HCV) infection after liver transplantation is almost universal and usually leads to chronic hepatitis with different degrees of severity. The pathogenic mechanisms underlying the variable outcome of HCV infection recurrence are not well defined, but recent data suggest that the dynamics of HCV quasispecies may be involved. HCV quasispecies evolution was traced by longitudinal single strand conformation polymorphism, direct sequencing, and cloning analyses of pre- and post-transplant HCV-1b isolates from patients with histologically severe (seven cases) or mild or moderate (nine cases) HCV infection recurrence. Differences between the two groups of patients that concerned the level of viremia or the degree of HCV quasispecies complexity and diversity were not observed at any of the three time points analyzed. However, emergence of nucleotide and amino acid changes during the 12 months follow-up was significantly more frequent in patients with mild or moderate than in those with severe HCV infection recurrence. The ratio of non-synonymous to synonymous nucleotide substitutions 12 months after transplantation was also greater in the former, suggesting that the HVR1 of HCV is under stronger selective pressure in these subjects. These findings suggest that the degree of amino acid diversification in the HVR1 of HCV, which probably reflects the strength of immune pressure on HCV, is inversely related to the histological severity of HCV infection recurrence.

Influence of the genetic heterogeneity of the ISDR and PePHD regions of hepatitis C virus on the response to interferon therapy in chronic hepatitis C.

Two genomic regions of hepatitis C virus (HCV), the interferon sensitivity-determining region (ISDR) of the non-structural 5A gene (NS5A) and the protein kinase-RNA activated (PKR)-eukariotic transcription factor (eIF2-alpha) phosphorylation homology domain (PePHD) of the structural E2 gene, interact in vitro with the interferon-inducible cellular PKR protein kinase. Mutations within these regions might, therefore, influence the response to interferon therapy. Viral load at baseline and sequence heterogeneity of HCV in NS5A and E2 regions was studied in 74 HCV-1b and in 12 HCV-3a infected patients with chronic hepatitis C who were treated with interferon. As previously reported by us, in a smaller series of patients in which the ISDR region was analyzed [Saiz et al. (1998) Journal Infectious Diseases 177:839-847], in the present study a low viral load and a high number of amino acid mutations within the ISDR, but not within the PePHD region, were significantly associated with long-term response to interferon among HCV-1b infected patients. No relationship between these viral features and response to therapy was disclosed in patients infected with HCV-3a.

High amino acid variability within the NS5A of hepatitis C virus (HCV) is associated with hepatocellular carcinoma in patients with HCV-1b-related cirrhosis.

Interferon therapy may decrease the risk of hepatocellular carcinoma in patients with hepatitis C virus (HCV)-related liver cirrhosis. Interaction of the cellular protein kinase PKR with the PKR-binding domain (PKR-bd) of HCV-NS5A protein may affect cellular growth control and viral resistance to interferon therapy. Mutations within the PKR-bd, which comprises the interferon sensitivity determining region (ISDR), have been associated with interferon sensitivity. To determine whether or not there is an association between HCV heterogeneity and the presence of hepatocellular carcinoma, HCV-1b genomic regions were amplified and directly sequenced from serum samples obtained from 82 patients with liver cirrhosis, 53 with, and 29 without hepatocellular carcinoma. None of them had received antiviral therapy. When compared with the deduced consensus sequence, the median number of amino acid changes in the PKR-bd was higher among samples from patients with (4.22) than from those without hepatocellular carcinoma (1.62; P <.001), and isolates with 3 or more amino acid changes were significantly more common among the former (60%) than among the later (6%, P <.001). No such differences were observed in other viral regions, including Core, E2-HVR-1, E2-PePHD, NS3, and the 5' and 3' PKR-bd flanking regions. In addition, amino acid variation in viral regions other than HVR-1 did not accumulate over time in the analyzed sequential serum samples obtained from patients with or without hepatocellular carcinoma. Therefore, a mutated HCV-PKR-bd phenotype is very common in cirrhotic patients with hepatocellular carcinoma.