Influence of HFE gene polymorphism on the progression and treatment of chronic hepatitis C

Summary.  We analysed liver histology findings in a large cohort of patients with chronic hepatitis C and in roughly half of them their response to interferon- α -based on iron parameters and HFE status. Histological activity and virological response to antiviral therapy ( n  = 146) were analysed in 273 immunocompetent and nonalcoholic patients with chronic hepatitis C, in terms of serum iron load, intrahepatic iron load ( n  = 110) and HFE mutations. Patients who were heterozygous for the C282Y and H63D mutations exhibited higher iron serum parameters than subjects without these mutations. The intrahepatic iron load was higher in H63D patients only. No association was observed between HFE mutations and histological activity. Increased iron parameters were associated with liver disease severity by univariate analysis only. Genotype 1 and ferritinaemia were associated with a poor response to antiviral therapy, whereas the H63D mutation emerged as a positive predictive factor for end of treatment and sustained antiviral response. Therefore, in chronic hepatitis C patients serum and intrahepatic iron levels were weakly correlated with histological activity, while HFE mutations were not. As for the response to interferon- α , elevated ferritinaemia constituted a negative predictive factor whereas the H63D mutation was a positive one. The H63D mutation might form part of an immunogenetic profile influencing the response to interferon therapy.     

Anemia associated with antiviral therapy in chronic hepatitis C: incidence, risk factors, and impact on treatment response.

BACKGROUND: One major side effect of combination antiviral therapy is the development of anemia, which is more severe among the Asian population. We conducted this large-scaled study to explore the incidence, risk factors, and impact on treatment response of anemia in chronic hepatitis C patients receiving combination antiviral therapy. METHODS: Four hundred and sixty-six chronic hepatitis C patients were treated with interferon-alpha-2b (IFN-alpha-2b) three or five million units thrice weekly, or pegylated-IFN-alpha-2b 1-1.5 microg/kg weekly plus ribavirin (1000-1200 mg/day) for 24 weeks. Severe anemia was defined as hemoglobin concentration <10 g/dl. RESULTS: The mean decrease of hemoglobin was 3.9+/-1.3 g/dl. Thirty-nine percent of patients had developed severe anemia during therapy. Stepwise logistic regression analysis revealed that old age (> or =50 years) (odds ratio [OR]=1.935, P=0.001) and baseline hemoglobin level (> or =14 g/dl) (OR=2.975, P<0.001) were significantly correlated with maximal decreases in hemoglobin. Using Cox's regression analysis, pretreatment platelet counts (<150 000/mm(3)) (OR=1.821, P<0.001), old age (> or =50 years) (OR=1.789, P=0.001), female gender (OR=1.739, P<0.001), and low body weight (<65 kg) (OR=1.493, P=0.027) were independent factors contributing to severe anemia. There was a significant linear correlation between the sustained virological response (SVR) rate and the time of severe anemia during therapy (r=0.774, P=0.003), especially among genotype 1 patients (r=0.960, P<0.001). CONCLUSION: Careful monitoring of hemoglobin level is necessary in patients who are old, female and have low body weight and platelet counts. Development of severe anemia was significantly correlated with the SVR.     

IL28B polymorphism as a predictor of antiviral response in chronic hepatitis C

AIM:To evaluate the effect of single nucleotide polymorphisms of interleukin(IL)-28B,rs12979860 on progression and treatment response in chronic hepatitis C.METHODS:Patients(n = 64;37 men,27 women;mean age,44 ± 12 years) with chronic hepatitis C,genotype 1,received treatment with peg-interferon plus ribavirin.Genotyping of rs12979860 was performed on peripheral blood DNA.Histopathological assessment of necroinflammatory grade and fibrosis stage were scored using the METAVIR system on a liver biopsy sample before treatment.Serum viral load,aminotransferase activity,and insulin level were measured.Insulin resistance index,body mass index,waist/hip ratio,percentage of body fat and fibrosis progression rate were calculated.Applied dose of interferon and ribavirin,platelet and neutrophil count and hemoglobin level were measured.RESULTS:A sustained virological response(SVR) was significantly associated with IL28B polymorphism(CC vs TT allele:odds ratio(OR),25;CC vs CT allele:OR,5.4),inflammation activity(G 1 vs G 1:OR,3.9),fibrosis(F 1 vs F 1:OR,5.9),platelet count( 200 × 10 9 /L vs 200 × 10 9 /L:OR,4.7;OR in patients with genotype CT:12.8),fatty liver(absence vs presence of steatosis:OR,4.8),insulin resistance index( 2.5 vs 2.5:OR,3.9),and baseline HCV viral load( 10 6 IU/mL vs 10 6 IU/mL:OR,3.0).There was no association with age,sex,aminotransferases activity,body mass index,waist/hip ratio,or percentage body fat.There was borderline significance(P = 0.064) of increased fibrosis in patients with the TT allele,and no differences in the insulin resistance index between groups of patients with CC,CT and TT alleles(P = 0.12).Spearman's rank correlation coefficient between insulin resistance and stage of fibrosis and body mass index was r = 0.618 and r = 0.605,respectively(P 0.001).Significant differences were found in the insulin resistance index(P = 0.01) between patients with and without steatosis.Patients with the CT allele and absence of a SVR had a higher incidence of requiring threshold dose reduction of interferon(P = 0.07).CONCLUSION:IL28B variation is the strongest host factor not related to insulin resistance that determines outcome of antiviral therapy.Baseline platelet count predicts the outcome of antiviral therapy in CT allele patients.     

Genetic variability in hepatitis C virus and its role in antiviral treatment response

Hepatitis C virus (HCV) is a major health problem worldwide, infecting an estimated 170 million people. The high genetic variability of HCV contributes to the chronicity of hepatitis C. Here, we report results from a large-scale sequence analysis of 67 patients infected with HCV genotype 1, 23 with subtype 1a and 44 with subtype 1b. Two regions of the HCV genome were analysed in samples prior to combined therapy with alpha interferon plus ribavirin, one compressing the hypervariable regions (HVR1, HVR2 and HVR3) of the E2 glycoprotein and another one including the interferon-sensitive determining region (ISDR) and the V3 domain of the NS5A protein. Genetic diversity measures showed a clear tendency to higher genetic variability levels in nonresponder patients to antiviral treatment than in responder patients, although highly disperse values were present within each response group for both subtypes. A more detailed analysis of amino acid composition revealed the presence of several subtype-specific variants in a few positions, but no discriminating positions between responder and nonresponder patients were detected. Our results also revealed that most amino acid positions were highly conserved, especially for subtype 1a. We conclude that the outcome of the antiviral treatment might depend not only on the nature of one or a few independent positions, but more likely on the combination of several positions along the HCV genome. Moreover, the own host's ability to generate an appropriate systemic response, in combination with the action of antivirals, is also likely to be essential for treatment outcome.     

The rate of fibrosis progression is an independent predictor of the response to antiviral therapy in chronic hepatitis C

summary . The response to antiviral therapy and the rate of fibrosis progression in chronic hepatitis C virus (HCV) infection are related to common factors, including age and gender. The aim of this study was to evaluate the relationship between the rate of fibrosis progression and the sustained virologic response (SVR) to interferon (IFN)-based treatment. A total of 332 patients treated for chronic HCV infection were evaluated. Using multivariate logistic regression analysis, the impact of the rate of fibrosis progression (defined as the stage of liver fibrosis according to the Metavir system/duration of infection) on the rate of SVR (negative HCV RNA at least 6 months following the end of treatment), was determined. The median age of the patients was 44 (range 25–77) years, 64% were male, and 66% were infected with genotypes 1, 4, 5 or 6. The median rate of fibrosis progression was 0.083 (range 0–2) Metavir units/year; 158 patients (48%) had F2–F4 fibrosis. After a median of 48 (range 2–126) weeks of therapy (IFN, n =190; IFN and ribavirin, n =96; pegylated IFN, n =20; pegylated IFN and ribavirin, n =26), 93 patients (28%) achieved an SVR. In univariate analysis, the rate of SVR was higher in slow [< 0.083 Metavir units/year ( n =162)] than rapid progressors [≥ 0.083 Metavir units/year ( n =170)] (35% vs 22%, P =0.01). After controlling for age, gender, genotype, viral load, and treatment regimen and duration, the rate of fibrosis progression remained an independent predictor of SVR (slow vs rapid progressors, OR 2.74; 95% CI 1.27–5.92; P =0.01). Hence the rate of fibrosis progression is an independent predictor of SVR to IFN-based therapy in patients with chronic hepatitis C. This additional factor should be considered in economic models evaluating this condition.     

Relationship between serum HCV markers and response to interferon therapy in chronic hepatitis C

Hepatitis C virus is the most frequent cause of chronic non-A, non-B hepatitis, and the antibodies to structural and nonstructural proteins encoded by viral genome have been suggested to be markers of ongoing HCV infection. We studied the behavior of these antibodies during interferon therapy in 18 patients with chronic hepatitis C and also during a follow-up period of at least four years. A significant decrease of anti-HCV titer was found only in patients who had shown positive response to therapy and all of them were anti-HCV negative at the end of follow-up. Analysis by recombinant immunoblotting assay showed that only anti-c100 were affected by interferon therapy, whereas anti-c22 and anti-c33 were not modified. Using polymerase chain reaction to detect small amounts of HCV genome in serum, we could confirm that the behavior of HCV-RNA during and after interferon therapy is similar to that of anti-HCV and the loss of anti-c100 seems to be closely related to HCV-RNA disappearance from serum. Our patients with chronic hepatitis C were found to be of type 1b and 2, according to the recent score of Simmonds, and the clearance of serum HCV-RNA during treatment and its sustained negative status are closely related to genotype 2 and to long-term positive response to interferon.     

Predicting response to initial therapy with interferon plus ribavirin in chronic hepatitis C using serum HCV RNA results during therapy

In patients with chronic hepatitis C, 48 weeks of therapy with interferon (IFN) plus ribavirin results in a sustained virologic response of 40%. Preliminary analysis suggests that measuring HCV RNA at week 24, rather than week 12, might provide the best prediction of treatment response. To assess the clinical utility of serum HCV RNA determinations at different times during therapy as a predictor of a sustained virologic response we evaluated 912 treatment‐naïve patients. Patients were randomized to receive IFN‐α2b, 3 million units (MU) three times weekly (tiw), for 24 or 48 weeks with either ribavirin or placebo, and then followed for 24 weeks. Serum HCV RNA was measured at weeks 4 and 12 in patients treated for 24 weeks; at 4, 12, and 24 weeks during therapy in those treated for 48 weeks, and week 24 post‐therapy in all patients. Sustained response was defined as loss of serum HCV RNA at week 24 follow‐up. Other patients were considered virologic nonresponders. For patients receiving 48 weeks of combination therapy, detectable serum HCV RNA at week 24 predicted nonresponse (positive predictive value) in 99% of patients compared to 89% at week 12. In patients treated for 24 weeks, testing at week 12 was more predictive of nonresponse than testing at week 4 in the combination‐therapy group but not in the monotherapy group. Hence, for combination therapy, testing for serum HCV RNA as a predictor of nonresponse is most accurate at week 24 of therapy; a positive test correctly identified 99% of nonresponders.     

Viral kinetics in the treatment of chronic hepatitis C

Hepatitis C virus (HCV) is a major cause of chronic hepatitis and hepatic fibrosis, and chronic infection can frequently progress to cirrhosis, end-stage liver disease and hepatocellular carcinoma. Treatment with pegylated interferons (INFs) plus ribavirin has been shown to be more effective than pegylated INFs alone or standard INFs with or without ribavirin. The early response of HCV to treatment with peg-INF has been used to predict treatment outcomes in infected patients, emphasizing the importance of viral kinetics and genotyping in their treatment. Mathematic modelling of viral dynamics has shown the importance of optimal doses of drug, with early virologic response at week 12 predictive of sustained virologic response. Maintaining INF concentration above a therapeutically effective level is necessary to prevent viral rebound and subsequent treatment failure. Once-weekly dosing with peg-INF-alpha2a, which has a longer half-life than other forms of INF, plus daily dosing with ribavirin, has been shown to be effective in reducing viral load.     

Usefulness of combined measurement of serum bile acids and ferritin as additional prognostic markers to predict failure to reach sustained response to antiviral treatment in chronic hepatitis C

AIM: To investigate the relationship between serum levels of ferritin and bile acids (BA) and the response to antiviral treatment in chronic hepatitis C (HCV). METHODS: A retrospective study was carried out on 35 control volunteers and 50 patients receiving interferon alpha-2b alone or plus ribavirin for 48 weeks. These were classified as sustained responders (SR) for >6 months after therapy (n = 17), non-responders (NR) (n = 27) and relapsers (RL) (n = 6). Before treatment, serum ferritin levels were determined by immunoturbidometry, 3alpha-hydroxyl-BA levels (S-3alpha-OH-BA) were assayed enzymatically and total (desulfated, deglucuronidated and deamidated) BA concentrations (STBA) by gas chromatography-mass spectrometry. RESULTS: STBA were lower in controls than in patients (SR < NR + RL). The highest levels of cholic acid and chenodeoxycholic acid families were found in NR + RL. Levels of cholic acid family were similar in controls and SR, whereas those of chenodeoxycholic acid family were higher in SR than in controls. A significant correlation between STBA (but not S-3alpha-OH-BA) and ferritin was found. Apparent value to predict the absence of a sustained response was calculated by combining elevated ferritin (>300 microg/mL) and STBA or individual BA species at different cut-off values. The best degree of certainty (100% specificity) was obtained using STBA >15 microM. CONCLUSION: These results recommend that larger prospective trials should be performed in chronic HCV patients to evaluate the usefulness of combined measuring of STBA and ferritin as additional prognostic markers to predict the existence of a very low probability of a sustained response to the current standard treatment, i.e. pegylated interferon in combination with ribavirin.     

慢性丙型肝炎患者病毒基因型与IL-28B基因型分布

目的：了解慢性丙型肝炎患者白细胞介素-28B（IL-28B）基因型多态性分布的特点及其临床意义。方法在27例慢性丙型肝炎患者,分离外周血细胞DNA,采用IPLEX Gold法检测宿主IL-28B基因多态性;分析患者IL-28B基因型与血清丙型肝炎病毒（HCV）基因型、HCV RNA载量和肝功能指标的相关性。结果在27例慢性丙型肝炎患者中,感染HCV基因1型1例（3.7%）,1b基因型7例（25.9%）,其它基因型19例（19/27,70.4%）;在IL-28B基因型中,rs12979860 CC基因型、rs12980275 AA基因型及rs8099917 TT基因型共24例（88.9%）,而IL28B rs12979860 CT基因型、rs12980275 GA基因型和rs8099917 GT基因型共3例（11.1%）;在HCV基因1型或1b型感染者中,IL28B rs12979860 CC基因型、rs12980275 AA基因型和rs8099917 TT基因型占62.5%（5/8）,而HCV其他基因型感染者IL28B rs12979860 CC基因型、rs12980275 AA基因型和rs8099917 TT基因型占100%（19/19）;HCV基因1型或1b型感染者与HCV其他基因型感染者比,其IL28B rs12979860位点、rs12980275位点和rs8099917位点基因型分布有显著性差异（P＆lt;0.01）;IL-28B基因多态性分布与患者血清HCV RNA载量或肝功能指标的变化无显著性相关。结论本组慢性丙型肝炎患者HCV基因型大多为非1型;大多数感染者IL-28B基因为rs12979860 CC、rs12980275 AA和rs8099917 TT基因型。     

Predictors of sustained response, relapse and no response in patients with chronic hepatitis C treated with interferon-α

Summary. Three main patterns of response are seen when interferon-α (IFN-α) is used for the treatment of chronic hepatitis C: 1 sustained response with alanine-aminotransferase (ALT) normalization that is maintained after cessation of therapy, with or without clearance of serum hepatitis C virus (HCV) RNA; 2 transient response with ALT normalization during therapy followed by relapse after its withdrawal, and 3 no response with no or only partial reduction in ALT levels. In order to define variables that could predict each of these three types of response we studied 321 cases of chronic hepatitis C treated with IFN-α in two consecutive trials conducted in our Unit. By univariate analysis, age < 45 years (P < 0.01), known disease duration < 60 months (P < 0.01), normal gamma-glutamyltranspeptidase (γGT) levels (P < 0.01) and infection by HCV genotype 2 or HCV genotype 3 (P < 0.01) were found to be statistically associated with sustained response while age > 45 years (P < 0.01), body weight (P= 0.05), cirrhosis (P < 0.01) and elevated γGT levels (P < 0.01) were associated with no response. By multivariate analysis sustained response was predicted by HCV genotype 2 (P < 0.01) and HCV genotype 3 (P < 0.01), known disease duration (P < 0.01), patient's age (P < 0.05) and associated with the use of a more aggressive treatment schedule (P < 0.05). Transient response with relapse was predicted by known duration of disease (P < 0.05), HCV genotype 1 (P < 0.05) and female sex (P < 0.05). No response was statistically associated with elevated γGT levels (P < 0.01), higher body weight (P < 0.05) and with the less aggressive regimen of 3 MU of natural IFN-α given three times weekly for 6 months (P < 0.05). These results indicate that the HCV genotype as well as the schedule of treatment greatly affect the pattern of response to IFN in chronic hepatitis C and allow us to define criteria to predict which type of response is more likely in individual patients.     

Long-term liver histology improvement in patients with chronic hepatitis C and sustained response to interferon

A retrospective multicentre survey was conducted to evaluate, in patients with chronic hepatitis C, the long-term liver histological changes induced by interferon (IFN). A total of 112 patients (mean age 46.4 years) were studied. All patients had received a 6-12-month IFN-alpha course (6-18 MU/week) and had successively undergone clinical, biochemical and virological follow-up for at least 36 months (range: 36-76). In each patient, two liver biopsies had been performed: 1-6 months before treatment and, 12-76 months after its completion. In 87 patients with biochemical and virological sustained response persisting for 12 months after therapy, post-treatment liver necroinflammation and fibrosis mean(+/-SD) scores (Knodell index) were significantly lower than pretreatment scores (2.9 +/- 2.2 vs 6.8 +/- 2.9 and 0.8 +/- 1.0 vs 1.2 +/- 1.1, respectively; P < 0.01). In 25 patients who relapsed within 1 year, necroinflammation and fibrosis post-treatment mean scores were similar to pretreatment scores (7.4 +/- 3.2 vs 6.9 +/- 3.1 and 1.8 +/- 1.3 vs 1.6 +/- 1.2, respectively; P > 0.05). On an individual basis, necroinflammation decreased in 87% of sustained responders but only in 36% of relapsers (P < 0.001), whereas fibrosis decreased in 44% of sustained responders but only in 14% of relapsers (P < 0.001). In sustained responders with biopsies performed 12-23 months (n=34), 24-35 months (n=26) or more than 36 months (n=27) after treatment, a progressive decrease of mean necroinflammatory score was observed (-2.6 +/- 2.1, -4.1 +/- 3.4 and -5.2 +/- 3.7 points, respectively; P < 0.01). A similar pattern was observed in fibrosis score (-0.3 +/- 0.6, -0.3 +/- 0.7 and -0.7 +/- 0.9 points, respectively; P < 0.05). Hence, among chronic hepatitis C patients treated with IFN, those with a 12-month sustained response, unlike those who relapse, have a long-term progressive reduction and, in some cases, a complete regression of liver histological damage.     

Efficacy of consensus interferon in the treatment of chronic hepatitis C

BACKGROUND AND AIMS: Consensus interferon (CIFN) is a newly developed type I interferon. The aim of this study was to investigate the safety and efficacy of CIFN in the treatment of patients with chronic hepatitis C and to determine the predictors for sustained response. METHODS: Patients were randomized to receive 3 micrograms or 9 micrograms CIFN three times a week for 24 weeks, followed by 24 weeks of observation. Efficacy was assessed by normalization of serum transaminase levels and disappearance of serum hepatitis C virus (HCV)-RNA at the end of treatment and at 24 weeks after stopping treatment. Histologic response was defined as a decrease of at least two points in the Knodell necroinflammatory score at week 48 and was compared with baseline. RESULTS: There were no serious adverse effects related to CIFN therapy. Overall, 44% of patients receiving 3 micrograms and 48% of patients receiving 9 micrograms had normalization of serum transaminase levels and disappearance of HCV viremia at the end of treatment. At 24 weeks after stopping treatment, 16% of patients in receiving 9 micrograms and 12% of patients receiving 3 micrograms had sustained responses. The histologic responses in patients receiving 9 micrograms and those receiving 3 micrograms were 60% and 36%, respectively. The necroinflammatory score was significantly reduced from baseline to week 48 in both groups. In addition, bodyweight < 60 kg and pretreatment serum HCV-RNA level < 0.5 MEq/mL can serve as predictors for sustained response to CIFN treatment. CONCLUSIONS: These findings suggest that 9 micrograms CIFN is safe and effective in the treatment of patients with chronic hepatitis C.     

慢性丙型肝炎不同抗病毒药物治疗的临床观察分析

目的：评价慢性丙型肝炎（CHC）不同抗病毒药物及方案的疗效与副作用，以优化慢性丙型肝炎治疗策略、提高临床治愈率。方法：动态观察、比较经典治疗组（普通干扰素α/利巴韦林）与聚乙二醇化干扰素α-2a（PEG-IFNα-2a）／利巴韦林组的临床疗效及副作用。结果：PEG-IFNα-2a／利巴韦林组与经典治疗组比较，其快速应答率高，早期的不良反应相对少而轻，对不良反应的总体耐受性好，疗效高并且稳定。结论：PEG-IFNα-2a联合利巴韦林方案较优，治疗中密切观察处理不良反应、施行个体化治疗方案具有提高总体疗效的意义。     

The natural history and antiviral treatment of hepatitis C in haemophilia

People with haemophilia who received non-virucidally treated large-pool clotting factor before 1986 were infected with hepatitis C virus (HCV), previously referred to as non-A, non-B hepatitis. Approximately one-tenth of patients have been shown to clear infection naturally and shown persistently negative HCV PCR. Patients have been infected with genotypes 1, 2 and 3 reflecting the plasma donors in Northern Europe and the United States. Several studies have shown that HCV mono-infection has a very slow progression. Co-infection with human immunodeficiency virus (HIV), however, can hasten the progression to cirrhosis and liver failure. Genotype 1 and older age at first infection also increase the progression rate. Candidates with detectable HCV RNA are candidates for therapy. The combination of standard interferon-alpha and ribavirin doubles the effectiveness of interferon-alpha alone and is the current standard of care for the treatment of chronic hepatitis C. The duration of therapy depends on the genotype and level of viraemia. Patients with genotypes 2 or 3 should have 6 months' therapy while those with genotype 1 and > 2 million copies mL-1 should have 1 year of therapy. Pegylated interferon is an emerging therapy. Patients co-infected with HIV, in whom treatment has stabilized the HIV infection, may be able to tolerate therapy for HCV infection. Liver transplantation is indicated for patients with haemophilia who have decompensated hepatitis C infection.     

Predictive factors in eradicating hepatitis C virus using a relatively small dose of interferon

Interferon (IFN) can reduce hepatitis C virus load and even eliminate the virus in 30-40% of patients. Several predictive factors for eradication of the virus have been reported and a higher dose of IFN tends to result in elimination of the virus. However, a small dose of IFN sometimes is as effective as a large dose in eradicating the virus. The predictive factors for such a response are not well established. We retrospectively analysed 50 patients with chronic hepatitis C who were treated with relatively small amounts of IFN (equal or less than 252 million units). Eleven patients were responders (elimination of hepatitis C virus (HCV) and normalization of alanine amino transferase (ALT) for at least 6 months), but the remaining 39 were non-responders. Multivariate analysis showed that the pretreatment viral load and total dose of IFN per kilogram of bodyweight were significant predictive factors of response to therapy. We also assessed the amino acid substitutions in the IFN sensitivity determining region (ISDR), NS5A codon 2209-2248, of HCV in serum samples obtained from 31 patients with HCV genotype 1 b. The presence of more than one amino acid substitution in the ISDR tended to correlate with HCV genotype lb elimination. As IFN is expensive and has a number of serious side effects, our study suggests that the optimal dose of IFN may vary from one patient to another and that more stringent criteria should be used to select the optimal dose for therapy.     

A single nucleotide polymorphism of the low molecular mass polypeptide 7 gene influences the interferon response in patients with chronic hepatitis C

summary . Transporter associated with antigen processing (TAP) and low molecular mass polypeptides (LMP) play crucial roles in the human leukocyte antigen (HLA) class I-restricted antigen presenting systems. This study was performed to elucidate whether these antigen-presenting gene polymorphisms could influence the response to interferon (IFN) treatment in patients with chronic hepatitis C. Polymorphisms of TAP and LMP genes in 175 hepatitis C virus (HCV) patients were determined by polymerase chain reaction-restriction fragment length polymorphism. The frequencies of these genes were compared between sustained-responders ( n =49) and nonresponders ( n =126), classified by biochemical and virological responses to IFN. The distributions of TAP1*, TAP2*, and LMP2 genes between sustained-responders and nonresponders did not differ. However, LMP7-K gene frequency in sustained-responders was higher than that in nonresponders [odds ratio 2.3 (95% confidence interval 1.1–4.6); 16% vs 7.9%]. Multivariate analysis revealed that LMP7-K and HCV-RNA quantity were independent factors influencing the outcome of IFN therapy [4.5 (1.4–14); P =0.011, 0.40 (0.24–0.65); P =0.0003, respectively]. Furthermore, among patients with a low viral load (≤ 2.0 Meq/mL), the LMP7-K positive patients had an even higher ratio of sustained response compared to those without LMP7-K [5.9 (1.6–22); 82% vs 44%; P =0.0062]. These findings suggest that a single nucleotide polymorphism of LMP7 gene is one of the important host factors which independently influence the response to IFN in patients with chronic hepatitis C.