Predictive value of rapid virological response and early virological response on sustained virological response in HCV patients treated with pegylated interferon alpha-2a and ribavirin

BACKGROUND AND AIM: The therapeutic effect of pegylated interferon (peg-IFN)-alpha-2a combination with ribavirin on patients with chronic hepatitis C virus (HCV) infection is dependent on the rapidity of the virological response. The aim of this study was to investigate the predictive value of rapid virological response (RVR) and early virological response (EVR) on sustained virological response (SVR) in HCV patients treated with peg-IFN-alpha-2a and ribavirin. METHODS: The HCV genotypes of 105 patients with chronic hepatitis C were detected by enzyme-immunoassay. Patients received subcutaneous 180 microg peg-IFN-alpha-2a once weekly plus daily ribavirin. Patients with genotype 1 were treated for 48 weeks and patients with genotype 2 or 3 were treated for 24 weeks. HCV RNA was assessed by qualitative PCR at pretreatment, at weeks 4 and 12 during treatment, and at week 24 of follow-up. Virological response rates at different weeks were investigated, with RVR defined as serum HCV RNA undetectable after 4 weeks and EVR defined as HCV RNA either undetectable or decrease by >or=2 log(10) after 12 weeks. The effects of virological response rates at different weeks on SVR were analyzed. RESULTS: Of the 105 patients, 44 (41.9%) were genotype 1, 46 (43.8%) were genotype 2, and 15 (14.3%) were genotype 3. RVR rates (19.5%) of patients with genotype 1 were significantly lower than those (60.7%) of genotype 2 or 3 (chi(2) = 16.836, P = 0.000); and EVR rates (73.2%) of patients with genotype 1 were significantly lower than those (96.7%) of genotype 2 or 3 (chi(2) = 12.220, P = 0.000). The SVR rates (86.7%) of patients who had achieved RVR were significantly higher than those (43.9%) of patients who had not achieved RVR (chi(2) = 19.713, P = 0.000). The positive predictive value of RVR in all patients was higher than that of EVR, but there was no significant difference between RVR and EVR. The negative predictive value of RVR in all patients or with genotype 1 was significantly lower than that of EVR. In univariate analysis, HCV RNA level (P = 0.014), genotype (P = 0.001), RVR (P = 0.000) and EVR (P = 0.000) were associated with effect of treatment. However, in stepwise regression analysis, the independent factors associated with effect of antiviral therapy were RVR (OR = 6.501, P = 0.001), EVR (OR = 2.776, P = 0.003) and genotype (OR = 3.061, P = 0.024). CONCLUSIONS: The RVR and EVR rates of patients with genotype 1 were significantly lower than those of patients with genotype 2 or 3. RVR had a similar predictive value as EVR on SVR. Genotype, HCV RNA level, RVR and EVR were associated with SVR. Genotype, RVR and EVR were independent factors for predicting the effect of antiviral therapy.     

Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon alpha-2a (40 kd)/ribavirin therapy

Approximately one third of hepatitis C virus (HCV) genotype 1 patients achieved a sustained virological response (SVR) after 24 weeks of treatment with peginterferon alpha-2a (40 kd) plus ribavirin in a randomized, multinational trial. We aimed to identify factors associated with a rapid virological response (RVR) at week 4 (HCV RNA <50 IU/mL) and a SVR (HCV RNA <50 IU/mL at the end of follow-up) in these patients. Stepwise multiple logistic regression analysis was used to explore the prognostic factors for a RVR and SVR in genotype 1 patients treated for 24 weeks. Fifty-one of 216 (24%) genotype 1 patients in the 24-week treatment groups had a RVR. SVR rates were considerably higher in patients with than without [corrected] a RVR (89% vs. 19%, respectively). Patients with a baseline HCV RNA of less than 200,000 IU/mL (OR 9.7, 95% CI 4.2-22.5; P < .0001) or 200,000-600,000 IU/mL (OR 5.6, 95% CI 1.5-9.1; P = .0057) were more likely to achieve a RVR than those with HCV RNA greater than 600,000 IU/mL. HCV subtype (1b vs. 1a) was also independently associated with RVR (OR 1.8, 95% CI 0.9-3.7; P = .0954). RVR (OR 23.7 vs. no RVR, 95% CI 9.1-61.7) and baseline HCV RNA less than 200,000 IU/mL (OR 2.7 vs. > 600,000 IU/mL, 95% CI 1.1-6.3; P < .026) were significant and independent predictors of SVR in patients treated for 24 weeks. In conclusion, patients infected with HCV genotype 1 and treated with peginterferon alpha-2a/ribavirin sustained a RVR 24% of the time. This portends an 89% probability of a SVR after 24 weeks of treatment.     

Role of interleukin-28B polymorphisms in the treatment of hepatitis C virus genotype 2 infection in Asian patients

Genome-wide association studies have linked single nucleotide polymorphisms (SNPs) near the interleukin-28B gene to the hepatitis C virus genotype 1 (HCV-1) response to peginterferon/ribavirin treatment. We aimed to explore the impact on the treatment outcomes of Asian HCV-2 patients. We determined rs8105790, rs8099917, rs4803219, and rs10853728 to be candidate SNPs in 482 Asian HCV-2 patients treated with the standard of care. Because the first three SNPs were in very strong linkage disequilibrium with one another (r2 = 0.94-0.96), rs8099917 and rs10853728 were selected for an analysis of their influence on the achievement of rapid virological response [RVR; seronegativity for hepatitis C virus (HCV) RNA in treatment week 4] and sustained virological response (SVR; seronegativity for HCV RNA throughout 24 weeks of posttreatment follow-up). The rs10853728 genotype did not predict RVR or SVR in HCV-2 patients. However, patients with the rs8099917 TT genotype, in comparison with patients with GT/GG genotypes, had a significantly higher rate of achieving RVR (85.2% versus 72.0%, P = 0.017) but did have not a significantly higher rate of achieving SVR (89.4% versus 86.0%). Multivariate analysis revealed that a baseline HCV viral load <400,000 IU/mL was the strongest predictor of RVR [odds ratio (OR) = 4.27, 95% confidence interval (CI) = 2.31-7.87, P < 0.001], and this was followed by advanced liver fibrosis (OR = 0.28, 95% CI = 0.15-0.53, P < 0.001), the carriage of the rs8099917 TT genotype (OR = 3.10, 95% CI = 1.34-7.21, P = 0.008), and the pretreatment level of aspartate aminotransferase (OR = 0.996, 95% CI = 0.99-1.00, P = 0.04). Nevertheless, the achievement of RVR was the single predictor of SVR with an OR of 19.37 (95% CI = 8.89-42.23, P < 0.001), whereas the rs8099917 genotypes played no role in achieving SVR with or without RVR. CONCLUSION: The rs8099917 TT genotype is significantly independently predictive of RVR, which is the single best predictor of SVR, in Asian HCV-2 patients.     

Factors affecting efficacy in patients with genotype 2 chronic hepatitis C treated by pegylated interferon alpha‐2b and ribavirin: reducing drug doses has no impact on rapid and sustained virological responses

Summary. Reducing the dose of drug affects treatment efficacy in pegylated interferon (Peg‐IFN) and ribavirin combination therapy for patients with hepatitis C virus (HCV) genotype 1. The aim of this study was to investigate the impact of drug exposure, as well as the baseline factors and the virological response on the treatment efficacy for genotype 2 patients. Two‐hundred and fifty patients with genotype 2 HCV who were to undergo combination therapy for 24 weeks were included in the study, and 213 completed the treatment. Significantly more patients who achieved a rapid virological response (RVR), defined as HCV RNA negativity at week 4, achieved a sustained virological response (SVR) (92%, 122/133) compared with patients who failed to achieve RVR (48%, 38/80) (P < 0.0001). Multivariate logistic‐regression analysis showed that only platelet counts [odds ratio (OR), 1.68; confidence interval (CI), 1.002–1.139] and RVR (OR, 11.251; CI, 5.184–24.419) were independently associated with SVR, with no correlation being found for the mean dose of Peg‐IFN and ribavirin for RVR and SVR. Furthermore, in the stratification analysis of the timing of viral clearance, neither mean dose of Peg‐IFN (P = 0.795) nor ribavirin (P = 0.649) affected SVR in each group. Among the patients with RVR, the lowest dose group of Peg‐IFN (0.77 ± 0.10 μg/kg/week) and ribavirin (6.9 ± 0.90 mg/kg/day) showed 100% and 94% of SVR. Hence, RVR served as an important treatment predictor, and drug exposure had no impact on both SVR and RVR in combination therapy for genotype 2 patients.     

Rapid Virological Response Represents the Highest Prediction Factor of Response to Antiviral Treatment in HCV-Related Chronic Hepatitis: a Multicenter Retrospective Study

Background:

Standard [i.e. pegylated interferon (Peg-IFN) + ribavirin] treatment of hepatitis C virus (HCV)-related chronic hepatitis is associated with a sustained virological response (SVR) in 50 - 90% of patients. A rapid virological response (RVR) (i.e. negative HCV-RNA after 4 weeks of treatment) predicts SVR in almost 90% of patients.

Objectives:

The main aim of this study was to assess the strength of RVR, as a predictive factor of antiviral treatment response.

Patients and Methods:

Using univariate and multivariate analysis, we retrospectively evaluated biochemical, metabolic, genetic and viral variables that might affect both RVR and SVR to Peg-IFN plus ribavirin, in 315 consecutive outpatients affected by HCV-related chronic hepatitis.

Results:

At univariate analysis, staging, body mass index, RVR, genotype and viral load were significantly related to SVR (P < 0.001). At multivariate analysis, RVR and genotype remained significant (P < 0.00001). The RVR had a predictive value of 83%. At univariate and multivariate analyses, diabetes (P = 0.003), genotype 2 (P = 0.000) and HCV-RNA values (P = 0.016) were independent predictors of RVR, even though at multivariate analyses, only genotype 2 was significantly related to RVR. When we stratified patients, according to genotype, no laboratory or clinical factors were predictive of RVR in genotype 1 patients at either univariate or multivariate analysis. In genotype 2 patients, staging (P = 0.029) and diabetes (P = 0.001) were the only significant predictors of RVR at univariate analyses, whereas no factor was independently related to RVR, at multivariate analysis.

Conclusions:

The RVR is the strongest factor of SVR and infection with HCV genotype 2 is significantly associated with RVR. Neither biochemical and/or metabolic factors seem to exert influence on RVR.     

Hyperhomocysteinemia increases the risk of venous thrombosis independent of the C677T mutation of the methylenetetrahydrofolate reductase gene in selected Brazilian patients.

Fasting total homocysteine (tHcy) and the methylenetetrahydrofolate reductase (MTHFR) C677T mutation were evaluated in 91 patients with venous thromboembolism and without acquired thrombophilia, and in 91 age-matched and sex-matched controls. Hyperhomocysteinemia was detected in 11 patients (12.1%) and in two controls (2.2%), yielding an odds ratio (OR) for venous thrombosis of 6.1 [95% confidence interval (CI), 1.3-28.4]. After excluding 21 patients and four controls with other known genetic risk factors for venous thrombosis, the OR was not substantially changed (7.0; 95% CI, 1.5-33.1). The prevalence of the MTHFR 677TT genotype was not significantly different in patients (9.9%) and in controls (5.5%), with an OR for venous thrombosis of 1.8 (95% CI, 0.6-5.8). Subjects with the MTHFR 677TT genotype showed higher levels of tHcy compared with the 677CC genotype in patients (P = 0.010) and in controls (P = 0.030). In conclusion, we found that fasting hyperhomocysteinemia is a risk factor for venous thrombosis in patients without known acquired thrombophilia and other genetic risk factors for venous thrombosis. Although tHcy levels are significantly higher in those homozygous for the MTHFR C677T mutation, this genotype does not increase the thrombotic risk in our study population.     

亚甲基四氢叶酸还原酶基因 C677 T多态性与中国山东地区汉族人群缺血性卒中、高尿酸血症的相关性

目的：探讨亚甲基四氢叶酸还原酶（methylenetetrahydrofolatereductase,MTHFR）基因C677 T 多态性与中国山东地区汉族人群缺血性卒中、高尿酸血症的相关性。方法纳入山东地区汉族急性缺血性卒中患者和年龄、性别相匹配的对照者。采用聚合酶链反应扩增和芯片杂交显色技术检测MTHFR基因C677T 多态性,并测定血清尿酸浓度。结果共纳入山东地区汉族急性缺血性卒中患者145例和年龄、性别相匹配的对照者145名。缺血性卒中组糖尿病构成比（26.90％对6.89％;χ2=20.653,P<0.001）以及空腹血糖[（5.56±1.57）mmol/L对（5.01±1.11）mmol/L;t=－3.390, P=0.001]、高半胱氨酸[中位数,四分位数间距：18.2（16.30~22.55）μmol/L对15.20（12.10~17.85）μmol/L;Z=－6.323,P<0.001]和尿酸[43.0（361.60~490.45）μmol/L对285.9（267.00~346.25）μm o l/L;Z=－10.360, P<0.001]水平均显著高于对照组;缺血性卒中组 T T 基因型（42.07％对15.17％;χ2=25.673, P<0.001）和 T 等位基因（58.28％对34.48％;χ2=33.008, P<0.001）分布频率均显著高于对照组。多变量logistic回归分析显示,尿酸[优势比（ odds ratio, OR）1.018,95％可信区间（confidence interval, CI）1.013~1.024;P<0.001]、TT 基因型（对CT 基因型, OR 6.774,95％CI 1.779~25.507;P=0.005）、高血压（ OR 1.919,95％CI 1.013~3.636;P=0.045）、高半胱氨酸（ OR 1.153,95％CI 1.059~1.258;P=0.001）为缺血性卒中的独立危险因素。将缺血性卒中组与对照组合并,共101例存在高尿酸血症,189例尿酸正常。高尿酸血症组糖尿病患者构成比（32.67％对11.64％;χ2=23.749, P<0.001）以及总胆固醇[（5.67±1.56）mmol/L对（5.10±1.33）mmol/L;t=－3.255,P<0.001]和高半胱氨酸[19.50（17.10~24.70）μmol/L对15.40（12.60~18.05）μmol/L;Z=－7.236,P<0.001]水平显著高于尿酸正常组,TT 基因型（55.45％对13.76％;χ2=56.409,P<0.001）和T等位基因（71.79％对32.54％;χ2=79.561,P<0.001）分布频率显著高于尿酸正常组。多变量logistic回归分析显示,TT 基因型（对CC 基因型,OR 6.434,95％CI 2.334~17.736;P<0.001）、CT 基因型（对CC基因型,OR 2.234,95％CI 1.019~4.898;P=0.045）、高半胱氨酸（OR 1.081,95％CI 1.010~1.157;P=0.024）、总胆固醇（OR 1.363,95％CI 1.123~1.653;P=0.002）为高尿酸血症的独立危险因素。结论 MTHFR基因C677T TT 基因型和血清尿酸水平是中国山东地区汉族人群缺血性卒中的独立危险因素,MTHFR基因C677T TT 基因型亦为该人群高尿酸血症的独立危险因素,调整饮食习惯可能对山东地区汉族人群缺血性卒中的预防具有积极意义。     

Hyperhomocysteinemia and the MTHFR C677T mutation in Budd-Chiari syndrome

Hyperhomocysteinemia (HH) is a factor that predisposes individuals to thrombosis, and the C677T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) is known to give increased plasma homocysteine. However, little is known about their roles in Budd-Chiari syndrome (BCS). This study evaluated the roles of HH and the MTHFR C677T mutation in patients with BCS. We compared 41 BCS patients with 80 sex- and age-matched healthy controls. The mean plasma homocysteine level was significantly higher in patients with BCS (20.15 +/- 5.78 micromol/L) compared with normal controls (15.80 +/- 6.58 micromol/L), P < 0.01. HH (>19.5 micromol/L in men and >15.0 micromol/L in women) was detected in 15 (36.59%) patients and in 14 (17.5%) controls (odds ratio [OR], 2.72; 95% confidence internal [CI], 1.17-6.32). The prevalence of the mutated MTHFR 677TT genotype and the 677T allele in normal controls was 10.0% and 31.3%, respectively. The mutant 677T homozygotes and alleles were more frequent in patients with BCS than in controls (22.0% vs. 10.0%, 0.025 < P < 0.05; 45.1% vs. 31.3%, 0.025 < P < 0.05). The relative risk of BCS among the carriers of 677TT was significantly increased (OR, 3.3; 95% CI, 1.1-10.0). The mutant MTHFR heterozygous 677C/T carriers were not significantly increased in patients with BCS compared with controls (46.3% vs. < 2.5%, P > 0.05). The relative risk OR of BCS among carriers of 677C/T was 1.6 (95% CI, 0.7-3.6). This study suggests that both HH and the homozygous C677T mutation in the MTHFR gene are important risk factors of BCS.     

New antiviral therapies for chronic hepatitis C

Chronic hepatitis C is an important health issue worldwide. The current standard therapy is based on a combination of pegylated-interferon (pegIFN) and ribavirin (RBV), but this treatment leads to only ~50% sustained virological response (SVR) in patients with HCV genotype 1 and high viral loads, who were mostly null-responders or relapsers. Among HCV genotypes other than HCV genotype 1, especially HCV genotype 4 patients show only 40–70% SVR by this treatment. Although new drugs also depend on the combination of pegIFN and RBV, it appears that these drugs improve not only rapid virological response (RVR) but also early virological response, leading to SVR in these patients. In the near future, we predict higher SVR rates in chronic hepatitis C patients treated with these new drugs.     

Role of hepatitis C virus substitutions and interleukin‐28B polymorphism on response to peginterferon plus ribavirin in a prospective study of response‐guided therapy

Recent studies have indicated that amino acid (aa) substitutions in the core region and NS5A interferon sensitivity‐determining region (ISDR) of hepatitis C virus (HCV) as well as genetic polymorphisms in the interleukin‐28B (IL‐28B) locus affect the outcome of interferon (IFN)‐based therapies. We aimed to investigate the role of these factors on response to peginterferon plus ribavirin in a prospective study of response‐guided therapy. The aa sequences in core region and ISDR and rs12979860 genotypes were analysed in 115 HCV‐1 patients. The treatment was 24 weeks for patients achieving a rapid virological response (RVR), 48 weeks for those with an early virological response (EVR) and early terminated in those without an EVR. A sustained virological response (SVR) was achieved in 82% of 34 RVR patients, 45% of 74 EVR patients and 0% of seven non‐EVR patients. Logistic regression analysis showed that ISDR mutation (≥2) [odds ratio(OR): 6.024], double core 70/91 mutations (OR: 0.136), and platelet counts ≥ 15 × 10⁴/μL (OR: 3.119) were independent pretreatment factors associated with SVR. Apart from rs12979860 CC genotype, low viral load and ISDR mutation (≥2) were significant factors predictive of RVR. Combination of rs12979860 genotype and baseline viral characteristics (viral load and core/ISDR mutations) could predict RVR and SVR with positive predictive value of 100% and 91%, and negative predictive value of 80% and 54%, respectively. In conclusion, pretreatment screening rs12979860 genotype and aa substitutions in the core region and ISDR could help identifying patients who are good candidates for peginterferon plus ribavirin therapy.     

IL‐28B polymorphisms and the response to antiviral therapy in HCV genotype 2 and 3 varies by ethnicity: a meta‐analysis

Studies of IL‐28B genotype in patients with hepatitis C virus (HCV) genotype 2/3 infection have yielded conflicting results. The aim of this meta‐analysis was to obtain a pooled odds ratio (OR) of the impact of IL‐28B genotype on achieving sustained virologic response (SVR) in patients with HCV genotype 2/3 infection treated with pegIFN and ribavirin. A meta‐analysis with a random effects model was performed, and study heterogeneity and publication bias were assessed. Forty‐three percent of the Caucasians (11 studies) and 86% of Asians (five studies) had the favourable IL‐28B genotype. In Caucasians, the pooled OR of SVR with the favourable IL‐28B genotype was 1.36 (95%CI: 0.98–1.88, P = 0.07) in all patients and 1.55 (95%CI: 1.10–2.18, P = 0.01) in patients treated with pegIFN and ribavirin for ≥24 weeks. In Asians, the pooled OR of SVR in patients with the favourable IL‐28B genotype was 1.99 (95%CI: 0.94–4.25, P = 0.07). The favourable IL‐28B genotype was also significantly associated with rapid virologic response (RVR) in both groups (Caucasians: OR: 1.82, 95%CI: 1.12–2.96, P = 0.02; Asians: 2.39, 95%CI: 1.39–4.11, P = 0.002), as well as the likelihood of an SVR in a subgroup of 350 Caucasian patients without an RVR (OR: 3.29, 95%CI: 1.67–6.51, P = 0.001). The favourable IL‐28B genotype is a statistically significant predictor of SVR and RVR in Caucasian patients treated with pegIFN and ribavirin for 24 weeks. In contrast, the favourable IL‐28B genotype is associated with RVR, but not SVR in Asian HCV genotype 2 patients.     

Pegylated interferon plus optimized weight‐based ribavirin dosing negate the influence of weight and body mass index on early viral kinetics and sustained virological response in chronic hepatitis C

Summary. Aim: Elevated body mass index (BMI) in chronic hepatitis C (CHC) has been associated with reduced rates of sustained virological response (SVR). The aims of this study were to determine whether early viral kinetics (and subsequently SVR) are influenced by weight or BMI by measuring HCV RNA at week 4 using two PCR assays with differing sensitivities. Methods: Patients with CHC treated with peginterferon plus weight‐based ribavirin were included in this retrospective study. Body mass index, pretreatment viral load, genotype and liver histology were abstracted from the clinical database. HCV RNA PCR (lower limit of detection (LLD) <50 IU/mL) at treatment week 4 and 6 months after completion of therapy were recorded to determine the presence of rapid virological response (RVR‐50) and SVR, respectively. In those who achieved RVR‐50, stored week 4 serum was retested using Taqman (LLD < 15 IU/mL, RVR‐15). Results: Of 134 patients included (genotype 1 57%, BMI 26.7 ± 4.5 kg/m², ribavirin dose 13.9 ± 2.6 mg/kg/day), 59% achieved SVR. RVR‐50 was observed in 39.6% and RVR‐15 in 27.6%. Neither body weight nor BMI influenced RVR‐50, RVR‐15 or SVR. The positive predictive values (PPVs) of RVR‐50 and RVR‐15 for SVR were 88.7% and 97.3% (P = 0.23). RVR‐50 and RVR‐15 superceded genotype and viral load as the strongest independent predictors of SVR (OR 9.25 (1.9–45.11) and OR 30.74 (3.08–317.96), respectively). Conclusions: RVR is the strongest predictor of SVR. Early viral kinetics is not influenced by body weight or BMI when weight‐based ribavirin is prescribed.     

Role of rapid virological response in prediction of sustained virological response to Peg-IFN plus ribavirin in HCV / HIV co-infected individuals

Summary.  The objective of the study was to evaluate the role of rapid virological response (RVR) in predicting sustained virological response (SVR) rates to hepatitis C virus (HCV) therapy. 65 HIV / HCV co-infected patients commenced HCV treatment per protocol. HIV / HCV patients with a mean CD4 count of 502 were treated for 24–48 weeks depending on genotype. Virological response was assessed at weeks 4 (RVR), 12 [early virological response (EVR)], 24, at end of treatment (EOTR) and 24 weeks post-completion of treatment (SVR). Primary end-point was defined as undetectable HCV RNA at 24 weeks post-treatment completion. Fifty-five per cent of co-infected patients were on highly active anti-retroviral therapy. A majority of patient group were male. 60% of HIV / HCV patients achieved SVR (35% genotype 1 / 4; 77% genotype 2 / 3). 24 HIV / HCV patients achieved undetectable HCV levels compared with baseline by week 4. The positive predictive value (PPV) of RVR at week 4 for subsequent SVR in HIV–HCV co-infected patients was 100%; the negative predictive value (NPV) was 57%. Significant variables associated with SVR were: (i) lower median pre-treatment HCV viral load, (ii) genotype 2 / 3 disease and (iii) achievement of RVR. Independent variables associated with RVR were low pre-treatment HCV viral load and genotype 2 / 3 disease. Achievement of RVR, a negative HCV-PCR, at week 4 of treatment is predictive of SVR in this cohort of patients. This may be used to guide optimal treatment duration in patient groups. More significantly, the data serve to highlight the subgroup of patients who, on achieving RVR, should be actively supported to complete HCV treatment with full dose therapy, especially patients co-infected with G2 / 3 disease for whom 6 months' full dose therapy may be sufficient to obtain a SVR.     

Effect of sustained virological response to treatment on the incidence of abnormal glucose values in chronic hepatitis C

BACKGROUND/AIMS: To investigate the effect of sustained virological response (SVR) on impaired fasting glucose (IFG) and/or type 2 diabetes (T2DM); to assess the influence of glucose abnormalities on the SVR rate. METHODS: 1059 patients with chronic HCV; normal glucose (< 100 mg/dl) in 734, IFG (between 100 and 125 mg/dl) in 218, and T2DM (126 mg/dl) in 107 cases, were treated with interferon plus ribavirin over 24 or 48 weeks, depending on viral genotype. RESULTS: The SVR rate was lower in patients with IFG and/or T2DM than in patients with normal glucose concentrations [143/325 (44%) vs. 432/734 (58.8%); P=0.002]. In the follow-up, abnormal glucose concentrations were observed in 74 of 304 (24.3%) non-responders and in 49 of 430 (11.4%) sustained responders (log-rank: 13.8; P=0.00002). Reverse stepwise logistic regression analysis identified the independent variables predictive of IFG or T2DM development as: sustained response (OR: 0.44; 95%CI=0.20-0.97; P=0.004) and fibrosis stage (OR: 1.46; 95%CI=1.06-2.01;P=0.02). Family history of DM, steatosis, gender, HCV viral load, genotype, triglycerides, cholesterol and BMI did not enter the multivariate analysis equation. CONCLUSIONS: SVR reduces the risk of IFG and/or T2DM development in patients with chronic hepatitis C while altered glucose metabolism impairs sustained response to viral treatment.     

The homeostasis model assessment of the insulin resistance score is not predictive of a sustained virological response in chronic hepatitis C patients

Objectives: To investigate the independent association between the homeostasis model assessment of the insulin resistance (HOMA‐IR) score and rapid virological response (RVR) and sustained virological response (SVR) in chronic hepatitis C (CHC). Methods: Observational prospective cohort study of 412 CHC patients [59% males; mean age 45 years; genotype 1 (44%), 2 (32%), 3 (19%) and 4 (5%)] treated with pegylated interferon α plus ribavirin. Results: A HOMA‐IR ≥2.0 was present in 49% and a metabolic syndrome in 4% of patients. By multivariate analysis, independent predictors of SVR were the lack of advanced fibrosis (≥F3) in genotype 1 and a lower body mass index in genotype 3 patients. In the subgroup of patients in whom HCV‐RNA was evaluated at week 4 (n=281), independent predictors of RVR were HCV‐RNA <700 000 IU/ml, age <40 years and lower aspartate aminotransferase:alanine aminotransferase ratio in genotype 1 and baseline HOMA‐IR ≤2 in genotype 3 patients. No predictive factor of RVR was identified among genotype 2 patients. RVR was the strongest predictor of SVR among genotype 1 or 3 patients. Conclusions: In this series of treatment‐naïve, Caucasian CHC patients at a low risk for the metabolic syndrome, HOMA‐IR is not a predictor of SVR, irrespective of the HCV genotype, although it may predict RVR in genotype 3 infection.     

ALOX5AP基因多态2354T/A和MTHFR基因多态677C/T的协同作用显著增加脑梗塞的易患性

目的研究MTHFR多态性和编码5-脂氧合酶激活蛋白的基因ALOX5AP多态性，尤其是基因之间的相互作用，是否与脑卒中的易患性相关。方法采用PCR．RFLP方法，对来自7个临床中心的1823名对照和1832名脑卒中患者检测了基因ALOX5AP和MTHFR的3个多态性，基因分型结果经测序进一步确证。多元logistic回归方法校正了传统危险因素后分析基因多态性与脑卒中的独立相关性。检测7个与脑卒中不相关的微卫星多态标记在病例一对照人群的频率分布以评估人群层化程度。结果MTHFR677TT基因型与男性脑梗塞的发病风险呈弱相关（OR，1．45；95％CI：1．04-2．02；P=0．020），ALOX5AP2354AA基因型也增加男性脑梗塞1．55倍的发病风险（95％CI：1．03．2．35；PP=0．038）。当个体同时携带MTHFR677TT和ALOX5AP2354AA基因型时，男性脑梗塞的相对患病风险率显著增加至3．58倍（（95％CI：1．72-7．43；P=0．001）。微卫星多态性标记的各主要等位基因片段的频率在病例和对照组无显著性差异。结论MTHFR677TT基因型和ALOX5AP2354AA基因型的协同作用与增加的男性脑梗塞患病风险呈显著相关。对于多因素复杂性疾病，综合分析弱效基因的相互作用有助于了解个体易患脑卒中的遗传背景。     

Twenty-four weeks of pegylated interferon plus ribavirin effectively treat patients with HCV genotype 6a

The optimal duration of treatment and expected response rate for hepatitis C virus genotype (HCV-6)-infected patients have not been determined. Our aims were to determine the treatment outcome with pegylated interferon (PEG-IFN) plus ribavirin for HCV-6a-infected patients at Southwest Hospital and assess the association of the on-treatment virological response with the sustained virological response (SVR). Medical records were reviewed retrospectively. Twenty-two HCV-6a-infected patients were treated for 24 weeks, and 21 (95.5%) achieved an early virological response (EVR), 20 (90.9%) an end-of-treatment response (ETR) and 18 (81.8%) a SVR. However, only 18 of the 22 HCV-6a-infected patients were tested for serum HCV RNA level at week 4 of treatment and 15 (83.3%) achieved a rapid virological response (RVR). The rates of SVR, RVR, EVR and ETR in these patients were all similar to those in HCV-2/3 treated for 24 weeks and higher than those in HCV-1b-infected patients treated for 48 weeks. A lower relapse rate (10.0%) was seen in HCV-6a compared with HCV-2/3 (12.5%) or HCV-1b-infected patients (23.3%). The positive predictive values of RVR and EVR for HCV-6a were comparable with those for HCV-2/3-infected patients (86.7%vs 90.9%, P = 0.683 and 85.7%vs 86.8%, P = 0.904, respectively). Of the 3 HCV-6a-infected patients who did not achieve a RVR, 2 achieved an EVR and went on to achieve a SVR. The patient who did not achieve an EVR did not achieve a SVR. In summary, our results indicate that 24 weeks of PEG-IFN plus ribavirin can effectively treat patients with HCV-6a chronic infection.     

Methylenetetrahydrofolate reductase (MTHFR) C677T genetic polymorphism and late infarct-related coronary artery patency after thrombolysis

In patients with acute myocardial infarction (AMI), a persistently occluded infarct-related artery (IRA) is associated with unfavorable prognosis and genetic factors may be contributing factors to thrombolysis failure. One-hundred and one consecutive patients treated with intravenous thrombolysis during AMI were blind-tested for methylenetetrahydrofolate reductase (MTHFR) and circulating homocysteine levels and underwent protocol angiography 14 ± 6 days after the event. IRA was patent in 61 patients and occluded in 40. Overall MTHFR 677TT frequency was 22%. Patients with MTHFR 677TT homozygosis had higher prevalence of occluded IRA (73%) versus those with MTHFR 677CT/CC genotype (30%, P < 0.001); MTHFR 677TT genotype predicted independently the risk of IRA occlusion with a specificity of 90% (odds ratio 3.8, 95% confidence interval 1.1–9.1; P = 0.03). Moreover, patients with occluded IRA and MTHFR 677TT genotype had the highest homocysteine levels (21 ± 7.6 μmol/l vs. ≤14.9 ± 3.8 μmol/l; P = 0.011). In patients with AMI, MTHFR 677TT homozygosis is independently associated with a persistently occluded IRA after thrombolysis. This finding may have pathophysiological and therapeutic implications for recanalization strategies in patients with AMI.     

老年慢性丙型肝炎患者抗病毒疗效及影响因素探讨

目的：探讨老年慢性丙型肝炎患者抗病毒疗效及影响因素。方法回顾性分析42例老年慢性丙型肝炎患者经聚乙二醇干扰素（Peg-IFNα-2a）联合利巴韦林治疗48周随访24周的病毒学应答、复发及无应答情况,分析与病毒学应答相关的影响因素。结果42例老年慢性丙型肝炎患者获得快速病毒学应答（RVR）、早期病毒学应答（EVR）、持续病毒学应答（SVR）比例分别为42．9％、78．6％、57．1％,复发率为26．2％,无应答率为21．4％。RVR组、EVR组的SVR为77．8％、72．7％,均高于非 RVR 组、非 EVR 组的41．7％、0（P 值分别为0．02、0．00）。SVR 组的病程（10．0±4．6）年、基线 HCV RNA（5．67±0．82）lg拷贝/mL、基因Ⅰ型占45．8％,显著低于非SVR组的（17．2±5．6）年、（6．39±0．92）lg拷贝/mL 和83．3％（P 值分别为0．00、0．02、0．01）;IL-28B 基因多态性 CC 等位基因为83．3％,明显高于非SVR组的50％（P＝0．02）。81％的老年慢性丙型肝炎患者感染途径是有手术史或输血史,78．6％的患者病程＞10年。结论老年慢性丙型肝炎患者可获得较高的病毒学应答率。感染 HCV 年限、基线 HCV RNA 载量、非基因Ⅰ型以及IL-28B等位基因CC型和RVR、EVR是预测抗病毒疗效的影响因素。     

Hyperhomocysteinemia and the MTHFR C677T polymorphism promote steatosis and fibrosis in chronic hepatitis C patients

The factors and mechanisms implicated in the development of hepatitis C virus (HCV)-related steatosis are unknown. Hyperhomocysteinemia causes steatosis, and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism induces hyperhomocysteinemia. We investigated the role of these factors in the development of HCV-related steatosis and in the progression of chronic hepatitis C (CHC). One hundred sixteen CHC patients were evaluated for HAI, fibrosis and steatosis grades, body mass index, HCV genotypes, HCV RNA levels, homocysteinemia, and the MTHFR C677T polymorphism. Hyperhomocysteinemia was associated with the TT genotype of MTHFR (r = 0.367; P = .001). Median values of homocysteine in the CC, CT, and TT genotypes of the MTHFR gene were 9.3, 12.2, and 18.6 micromol/L, respectively (P = .006). Steatosis correlated with the MTHFR polymorphism, homocysteinemia, HAI and fibrosis. Steatosis above 20% was significantly associated with fibrosis. Prevalence and high grade (>20%) of steatosis were 41% and 11% in CC, 61% and 49% in CT, and 79% and 64% in TT, respectively (P = .01). Relative risk of developing high levels of steatosis was 20 times higher for TT genotypes than CC genotypes. According to multivariate analysis, steatosis was independently associated with hyperhomocysteinemia (OR = 7.1), HAI (OR = 3.8), liver fibrosis (OR = 4.0), and HCV genotype 3 (OR = 4.6). On univariate analysis, fibrosis was associated with age, steatosis, MTHFR, homocysteinemia and HAI; however, on multivariate analysis, liver fibrosis was independently associated with age (P = .03), HAI (P = .0001), and steatosis (P = .007). In conclusion, a genetic background such as the MTHFR C677T polymorphism responsible for hyperhomocysteinemia plays a role in the development of higher degree of steatosis, which in turn accelerates the progression of liver fibrosis in CHC.