Baseline cholesterol is associated with the response to antiviral therapy in chronic hepatitis C

Background: Hepatitis C virus (HCV) partially interacts with low‐density lipoprotein (LDL) receptors, suggesting a role for lipids in regulating HCV clearance. Our aim was to study if baseline lipids can discriminate responders from non‐responders among patients with HCV infection. Methods: A total of 109 HCV patients were studied. Laboratory measurements included serum lipids, aminotransferases and viral load, as well as HCV genotype determinations. Results: Responders (n = 53) had significantly higher serum baseline levels of total cholesterol, LDL cholesterol and apolipoprotein B compared to non‐responders (n = 56). Multivariate logistic regression analysis showed that a 10 mg/dL increase in total cholesterol was associated with 3.02 higher odds of responding to treatment (95% CI 1.74–5.32, P < 0.001), while a 10 mg/dL increase in apolipoprotein B levels was associated with 1.81 higher odds of responding to treatment (95% CI 1.37–2.54, P < 0.001), after adjustment for age, sex, body mass index (BMI), smoking habits, baseline viral load, liver histology and administration of pegylated interferon. An inverse association between BMI and response to treatment was also evident (adjusted odds ratio 0.73, 95% CI 0.55–0.96; P = 0.03). Conclusion: Baseline serum total cholesterol levels and BMI could be helpful in discriminating responders to antiviral therapy among patients with HCV infection.     

Adherence to antiviral therapy in chronic hepatitis C

Adherence or compliance with the prescribed treatment regimen is an important factor that determines the success of therapy in chronic hepatitis C. A multidisciplinary team approach is required in order to educate and communicate effectively with the patient, individually tailor the prescribed regimen, provide organizational support, develop dispensing aids, and deal with side effects or psychosocial issues. Such measures can only improve patient confidence with the proposed treatment, hopefully resulting in improved healthrelated outcomes.     

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.     

Tumor necrosis factor genetic polymorphisms and response to antiviral therapy in patients with chronic hepatitis C

OBJECTIVE: Hepatitis C virus (HCV) is the major causal agent of non-A, non-B hepatitis and the leading indication for liver transplantation worldwide. The emerging field of immunogenetics has confirmed the significant role of heritability in host immune responses to infectious pathogens. Both the major and non-major histocompatibility complex genes are increasingly identified as candidate genes hypothesized to influence the susceptibility to, or the course of, a particular disease. We hypothesized that polymorphisms within the major histocompatibility complex class III region that encode for tumor necrosis factors (TNF)-alpha and TNF-beta might be predictive of response to antiviral therapy in patients with chronic hepatitis C. METHODS: A total of 155 subjects, including 110 HCV-seropositive individuals undergoing antiviral therapy and 45 ethnically similar HCV-negative controls, were studied. The HCV-positive patients had undergone antiviral treatment with either interferon monotherapy (n = 73) or in combination with ribavirin (n = 37) and were categorized as either nonresponders, sustained responders, or relapsers. Sixty (55%) patients had genotype 1 (1a or 1b). Genomic DNA was extracted, followed by polymerase chain reaction amplification and sequencing for two promoter TNF-alpha variants (at positions -238 and -308), as well as restriction fragment length analysis for four polymorphic loci within the TNF-beta gene (NcoI, TNFc, aa13, aa26). RESULTS: Although there was a trend toward higher frequency of the A allele in the TNF 238 promoter among HCV-infected patients (12% vs 4%), there were no significant differences in the distribution of the genotypic polymorphisms between patients and controls. Patients with the TNF 238 A allele had higher pretreatment viral loads as compared with patients homozygous for the wild type allele (7.2 x 10(6) +/- 4.2 x 10(6) copies/ml vs 3.8 x 10(6) +/- 0.34 x 10(6) copies/ml, p = 0.03). However, there was no association between TNF genetic markers, including multiple haplotypic combinations, and response to therapy. In addition, there was no correlation with these polymorphic loci and histological severity of liver disease. CONCLUSIONS: Although previous work has suggested potential roles for TNF in the pathogenesis of HCV infection, we were unable to identify any link between TNF genetic polymorphisms and histological severity or response to antiviral therapy.     

Association of serum interleukin-8 with virologic response to antiviral therapy in patients with chronic hepatitis C

BACKGROUND/AIMS: Upregulation of interleukin-8 by the hepatitis C virus non-structural-5A-protein leads to inhibition of the antiviral activity of interferon-alpha in vitro. The clinical significance of interleukin-8 levels for virologic response to interferon-alpha-based treatment in patients with chronic hepatitis C is unknown. METHODS: We investigated serum interleukin-8 in 59 healthy controls and 214 patients with chronic hepatitis C (genotype 1, n=152; genotype 2, 3, n=62) and different outcome to interferon-alpha-based therapy. RESULTS: In patients with chronic hepatitis C higher interleukin-8 levels were observed compared with healthy controls (P<0.0001). Hepatitis C genotype 1-infected patients with early and overall virologic response to interferon-alpha-based therapy showed lower interleukin-8 levels than non-responders (P=0.025 and P=0.035, respectively). In all patients, elevated interleukin-8 levels were associated with cirrhosis (genotype 1, P=0.0003; genotype 2, 3, P=0.009). Interleukin-8 levels in sustained virologic responders were still higher 24 weeks after the end-of-therapy compared with healthy controls (P<0.0001). CONCLUSIONS: In genotype 1 infected patients, low pretreatment serum interleukin-8 is associated with virologic response to interferon-alpha-based therapy. Thus, the conclusion from in vitro studies that the upregulation of interleukin-8 by the hepatitis C virus contributes to the inhibition of the antiviral actions of interferon-alpha may also be applicable in vivo.     

T-cell response relative to genotype and ethnicity during antiviral therapy for chronic hepatitis C

Viral genotype and host ethnicity are important predictors of viral clearance during antiviral therapy for chronic hepatitis C virus (HCV) infection. Based on the role of T cells in natural HCV clearance, we hypothesized that T cells may contribute to the genotypic and ethnic difference in treatment outcome. To test this hypothesis, T-cell response to HCV antigens (core, nonstructural NS3/4 and NS5) and control phytohemagglutinin (PHA) was monitored prospectively and was correlated with virological outcome in 41 patients chronically infected with HCV (27 genotype 1, 14 genotype 2 or 3; 19 black persons, 22 white persons) undergoing combined interferon alfa and ribavirin therapy. Interestingly, in patients with genotype 2 or 3 infection, enhanced virological response coincided with a greater T-cell response to HCV NS3/4 antigen at baseline (50% vs. 15%; P = .026) that augmented further during therapy (29% vs. 4%; P = .035) compared with genotype 1-infected patients. However, HCV-specific T-cell response remained weak in genotype 1-infected patients regardless of virological outcome or ethnicity. Furthermore, virological outcome was associated with a suppressed baseline proliferative response to phytohemagglutinin (P < .03) that increased during therapy (P < .003) independent of ethnicity or genotype. In conclusion, HCV-specific T-cell response was associated with HCV genotype but not with therapeutic clearance of HCV infection. The association between treatment outcome and phytohemagglutinin response suggests more global and antigen-nonspecific mechanisms for therapeutic HCV clearance.     

Hepatic vein transit times of a microbubble agent in assessing response to antiviral treatment in patients with chronic hepatitis C

Summary. Microbubble measurement of hepatic vein transit times (HVTT) may have the potential to assess severity of hepatitis C virus (HCV)‐related liver disease, where there is a shorter HVTT with more severe disease. We investigated the utility of this test as a marker of response to antiviral treatment. Thirty‐seven patients with biopsy‐proven HCV‐related disease undergoing antiviral treatment were studied. All had baseline scans and then repeat scans 6 months after the end of treatment. HVTT using Levovist were obtained from the right and middle hepatic veins, and the shorter time was used for analysis. The aspartate aminotransferase to platelet ratio index (APRI) scores were calculated retrospectively. There were seven patients with mild hepatitis, 23 with moderate/severe hepatitis and seven with cirrhosis. The mean baseline HVTT in responders ± SE increased from 27.3 ± 2.29 s to 33.5 ± 2.8 s posttreatment (P = 0.01). In the 10 nonresponders, the HVTT remained the same; 43.3 ± 9 s baseline compared to 44 ± 7.8 s posttreatment (P = 0.84). This trend was also seen with the APRI score where in responders, the mean score decreased from 1.1 ± 0.2 to 0.74 ± 1 (P = 0.03) and in nonresponders, the score remained unchanged; 0.88 ± 0.2 compared to 0.84 ± 0.2 (P = 0.31). HVTT measurement lengthened, while APRI scores decreased in patients who responded to antiviral treatment while both remained the same, shortened (HVTT) or increased (APRI), respectively, in patients who were nonresponders. These results are encouraging and indicate that these tests could be potentially used as markers of response to treatment and could obviate the need for serial biopsies in antiviral future treatment studies.     

外周血单个核细胞内HCV RNA是慢性丙型肝炎干扰素治疗效果的预测因子

目的 探讨慢性丙型肝炎干扰素(IFN)治疗结束时，外周血单个核细胞(PBMC)中HCV RNA检测对持续性应答的预测作用。方法 对因输血而感染的慢性HCV肝炎患者进行IFN治疗24周，在治疗12周即取得完全应答的患者，24周治疗结束时检测PBMC中HCV RNA，并对患者进行长期的血清HCV RNA监测。结果 治疗结束时，有9例患者的PBMC HCV RNA为阳性，7例为阴性。在PBMC中HCV RNA阳性患者，停止治疗的6个月内9例中8例血清HCV RNA阳转，1年内所有患者的HCV RNA复发。而PBMC HCV RNA阴性者，随访至停药6月时，7例中仅1例HCV RNA阳转，1年内共2例HCV RNA复发，其余5例，随访至3．5年，血清中HCV RNA仍阴性。结论 IFN治疗结束时PBMC中HCV RNA检测能预测慢性丙型肝炎的治疗效果。     

慢性丙型肝炎抗病毒治疗研究最新进展

基于长效干扰素和利巴韦林(ribavirin,RBV)的经典抗HCV疗法不良反应较大,疗效有待进一步提高.近年来抗HCV药物研发取得较快发展,以直接抗病毒药物(direct-acting antivirals,DAA)的研发最为活跃,在此基础上产生了多种新的抗HCV治疗策略.其中,针对病毒不同靶位的DAA联合治疗初露锋芒,Ⅱ期临床试验表明,不用干扰素,甚至不用RBV的DAA联合治疗可取得很好疗效,24周治疗后持续病毒学应答率最高可达100％,疗效可不受HCV基因型和患者IL-28B分型影响,患者耐受性通常良好.因此DAA联合治疗方案是今后治疗丙型肝炎的发展趋势.     

Individualisation of antiviral therapy for chronic hepatitis C

The combination of pegylated‐interferon (PEG‐IFN)/ribavirin is currently the standard of care antiviral treatment for chronic hepatitis C (CHC), but optimal results require an individual approach. Key issues are to deliver doses that confer optimal antiviral efficacy against hepatitis C virus (HCV) for a time sufficient to minimise relapse. Viral monitoring during therapy guides the subsequent treatment course, particularly HCV RNA results at 4 weeks (rapid viral response [RVR]) and 12 weeks (complete early viral response [cEVR]). There is strong evidence that for most patients with genotypes 2 or 3 HCV infection, RVR allows truncation of treatment to 16 weeks, provided ribavirin dose is weight‐based. However, those patients with cirrhosis, insulin resistance/diabetes or older than 50 years need 6–12 months treatment. For “difficult‐to‐treat” CHC (genotypes 1 and 4), RVR is infrequent (～15% in European studies), but allows treatment to be truncated from 48 to 24 weeks. Without RVR, there is some evidence that longer treatment (72 weeks) improves sustained viral response (SVR). However, “induction dosing” first 12 weeks of PEG‐IFN clearly does not improve SVR. To prevent dose reductions and complete therapy, it is critical to detect and treat depression and other disabling side‐effects, including judicious use of growth factors for severe anemia or neutropenia and possibly, thrombocytopenia. Another potentially important aspect may be attempts to counter central obesity and insulin resistance, which confer suboptimal antiviral response with any HCV genotype. Treatment partnerships with specialist nurses, psychological therapists and other healthcare workers are also essential for optimal individual management of patients with CHC.     

慢性丙型肝炎抗病毒治疗进展

抗病毒是治疗慢性丙型肝炎最重要的手段。叙述了近年来抗病毒治疗包括聚乙二醇干扰素和利巴韦林联合治疗、特异性靶点治疗、基因治疗等的进展情况。认为未来抗HCV治疗还需要更有效的药物联用治疗方式、更短的用药疗程、更低的毒副作用以及更高的耐药阈值等。     

Hepatic gene expression and prediction of therapy response in chronic hepatitis C patients

Chronic hepatitis C (HCV) infection remains a major health problem worldwide. The current standard of care is a combination of pegylated interferon-alpha and ribavirin. Considering the length of antiviral therapy, as well as its side effects and costs, accurate prediction of treatment response prior to initiation of treatment is critical. In addition to viral, demographic and environmental factors, host genetic diversity is believed to contribute to the spectrum of clinical outcomes of chronic HCV. The development of high-throughput technologies provides opportunities to define patterns of gene expression that are associated with certain disease outcomes and/or response to therapy. This article reviews genomics-based predictors of pre-treatment response to antiviral therapy.     

Factors associated with the response to interferon-based antiviral therapies for chronic hepatitis C

Hepatitis C virus(HCV) infection is a major health concern worldwide. Interferon-α(IFN-α) therapy has been the main antiviral treatment for more than 20 years. Because of its established antitumor effects, IFNbased treatments for chronic HCV infection still have a clinical impact, particularly for patients with high risk conditions of developing hepatocellular carcinoma, such as older age and advanced liver fibrosis. As a result of exhaustive research, several viral factors, including NS5 A amino acid mutations such as the IFN sensitivitydetermining region and the IFN/ribavirin resistancedetermining region, and mutations of amino acids in the core protein region(core 70 and 91) were shown to be associated with the response to IFN-α treatment. In addition, among the host factors related to the response to IFN-α treatment, polymorphisms of the interleukin-28 B gene were identified to be the most important factor. In this article, we review the factors associated with the efficacy of IFN-α treatment for chronic HCV infection. In addition, our recent findings regarding the possible involvement of anti-IFN-α neutralizing antibodies in a non-response to pegylated-IFN-α treatment are also described.