Association of HCV-related mixed cryoglobulinemia with specific mutational pattern of the HCV E2 protein and CD81 expression on peripheral B lymphocytes.
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Antigens, CD↗
Biomedical subjects
Christoph Sarrazin
Publications and source records attributed to Christoph Sarrazin.
Does noninvasive staging of fibrosis challenge liver biopsy as a gold standard in chronic hepatitis C?
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Aspartate Aminotransferases↗
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.
Adult↗
Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 3.
BACKGROUND/AIMS: Treatment duration in patients with chronic hepatitis C in the era of standard interferon-alpha plus ribavirin was tailored according to hepatitis C virus (HCV) genotype: patients infected with HCV-1 were treated for 48 weeks, patients infected with HCV-2/3 for 24 weeks. The aim of the present study was to investigate this schedule for HCV-2/3 infected patients in the era of pegylated interferon-alpha plus ribavirin. METHODS: Patients chronically infected with HCV-2 (n=42) or HCV-3 (n=182) were treated with peginterferon alfa-2b 1.5 microg/kg subcutaneously once weekly plus ribavirin 800-1400 mg/day based on body weight for 24 weeks. RESULTS: The end of treatment (EOT) and sustained virologic response (SVR) was higher in patients infected with HCV-2 (100 and 93%, respectively) than in patients infected with HCV-3 (93 and 79%, respectively). Baseline viremia (P=0.020), treatment duration >16 weeks (P<0.001) and steatosis (<5%, P=0.015) were significant independent predictors of SVR. Adverse events resulted in discontinuation in 5% and dose reduction in 22% of patients. CONCLUSIONS: Treatment for 24 weeks with peginterferon alfa-2b and ribavirin is sufficient in HCV 2 or 3 infected patients. The lower SVR in patients infected with HCV-3 compared with HCV-2 infected patients may be related to higher levels of steatosis in this population.
Adult↗
Influence of interleukin 12B (IL12B) polymorphisms on spontaneous and treatment-induced recovery from hepatitis C virus infection.
BACKGROUND/AIMS: Interleukin-12 (IL-12) governs the Th1-type immune response, affecting the spontaneous and treatment-induced recovery from HCV-infection. We investigated whether the IL12B polymorphisms within the promoter region (4 bp insertion/deletion) and the 3'-UTR (1188-A/C), which have been reported to influence IL-12 synthesis, are associated with the outcome of HCV infection. METHODS: We analyzed 186 individuals with spontaneous HCV clearance, 501 chronically HCV infected patients, and 217 healthy controls. IL12B 3'-UTR and promoter genotyping was performed by Taqman-based assays with allele-specific oligonucleotide probes and PCR-based allele-specific DNA-amplification, respectively. RESULTS: The proportion of IL12B promoter and 3'-UTR genotypes did not differ significantly between the different cohorts. However, HCV genotype 1-infected patients with high baseline viremia carrying the IL12B 3'-UTR 1188-C-allele showed significantly higher sustained virologic response (SVR) rates (25.3% vs. 46% vs. 54.5% for A/A, A/C and C/C) due to reduced relapse rates (24.2% vs. 12% vs. zero % for A/A, A/C and C/C). CONCLUSIONS: IL12B 3'-UTR 1188-C-allele carriers appear to be capable of responding more efficiently to antiviral combination therapy as a consequence of a reduced relapse rate. No association of IL12B polymorphisms and self-limited HCV infection could be demonstrated.
3' Untranslated Regions↗
Mutations within the CD81-binding sites and hypervariable region 2 of the envelope 2 protein: correlation with treatment response in hepatitis C virus-infected patients.
The hepatitis C virus (HCV) envelope 2 (E2) protein interacts with the cellular receptor CD81 in vitro. Within E2, 2 CD81-binding sites were described. E2-CD81 interaction has been shown to modulate B and T cell function. The clinical importance of mutations within the CD81-binding sites and overlapping hypervariable region 2 (HVR2) in correlation with response to antiviral treatment is unknown. Fifty-five patients infected with HCV-1b or HCV-3a underwent interferon-alpha-based treatment. The E2 gene, comprising the CD81-binding sites and HVR2, was sequenced from pretreatment serum samples. The number of mutations within CD81-binding sites was not correlated with virologic treatment response in HCV-1b- and HCV-3a-infected patients. Within HVR2, the total number of mutations was significantly higher in HCV-1b-infected patients with a sustained response to interferon-alpha-based treatment (3.9; range, 1-6) than in those with relapse (2.9; range, 1-5) or those who did not respond (2.8; range, 1-5) (P = .041). However, when the same analyses were based only on functionally nonconserved mutations, no significant differences were observed.
Adult↗
Apolipoprotein E4 allele is associated with poor treatment response in hepatitis C virus (HCV) genotype 1.
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Alleles↗
Twelve weeks of follow-up is sufficient for the determination of sustained virologic response in patients treated with interferon alpha for chronic hepatitis C.
BACKGROUND/AIMS: The current standard for the determination of sustained virologic response in patients treated for hepatitis C is undetectable hepatitis C virus (HCV) RNA 24 weeks following the completion of therapy. Sensitive molecular tests may permit earlier determination of sustained virologic response following the completion of therapy in end-of-treatment responders. METHODS: We examined this possibility in 1441 patients, who received 48 weeks of treatment with either standard or pegylated interferon alpha-2a. HCV RNA was determined by polymerase chain reaction assay (Amplicor HCV Monitor vs. 2.0) at baseline and monitored at 4-week intervals throughout the treatment and 24-week post-treatment follow-up periods. RESULTS: End-of-treatment and sustained response were achieved in 624 and 342 patients, respectively. For all treatments, relapse was most frequent at weeks 52 and 56 and became rare following week 60. Only six patients out of 348 patients (2%) became HCV RNA positive between weeks 60 and 72. Analysis of baseline characteristics failed to identify a specific set of parameters associated with early relapse. CONCLUSIONS: This finding suggests that determination of HCV RNA levels at 12 weeks of follow-up may be sufficient for making decisions related to the management of most patients treated with standard or pegylated interferon alpha.
Adult↗
Prediction of treatment outcome in patients with chronic hepatitis C: significance of baseline parameters and viral dynamics during therapy.
In patients with chronic hepatitis C virus (HCV) infection scheduled for a 48-week treatment period, premature discontinuation of treatment was previously recommended if HCV-RNA levels remained detectable at week 24 of therapy. Considering the number of side effects and treatment costs, measurement of initial viral decline during therapy may identify virologic nonresponse earlier than 24 weeks. We retrospectively analyzed 260 European patients treated with standard or pegylated interferon alfa (IFN-alpha) and ribavirin for 24 to 48 weeks. Early prediction of virologic response by HCV-RNA decline at weeks 4 and 12 (Versant Quantitative [branched DNA (bDNA) 3.0]; Bayer Diagnostics, Emeryville, CA; and Qualitative [transcription-mediated amplification (TMA)] HCV RNA assay; Bayer Diagnostics) as well as clinical, biochemical, virologic, and histologic baseline parameters were analyzed by logistic regression and receiver operating characteristic (ROC) curves. A viral load at treatment week 4 above 450,000 IU/mL and at week 12 above 30,000 IU/mL was 100% predictive for virologic nonresponse in all patients. From multivariate logistic regression analysis of all patients, independent predictors for sustained virologic response were: genotypes 2 and 3 (P <.0001), a low baseline gamma-glutamyltransferase (GGT) level (P <.0001), a high baseline alanine aminotransferase level (P =.002), and a low baseline viral load (P =.04). None of the latter 3 factors were predictive for sustained virologic response when analysis was restricted to the subgroup of genotypes 2- and 3-infected patients. In conclusion, virologic nonresponse can be predicted early at week 12 of treatment independent from the applied therapeutic regimen based on a cutoff level for HCV RNA of 30,000 IU/mL. This algorithm recognizes 53.7% of nonresponders previously identified at week 24 of treatment.
Adult↗
Highly sensitive hepatitis C virus RNA detection methods: molecular backgrounds and clinical significance.
After treatment of chronic hepatitis C virus (HCV), infection with interferon-alpha+/-ribavirin in a considerable proportion of patients with a virologic end-of-treatment response (ETR), a relapse during follow-up is observed. The biological background of relapse is unknown. Either antiviral therapy leads to a complete replication arrest and latent virions survive until the end-of-treatment or replication is not completely suppressed. For the latter hypothesis, residual HCV RNA should be detectable dependent on the sensitivity of the HCV RNA assay. In patients from different studies, serum or plasma samples from the end-of-treatment were investigated for the presence of HCV RNA with a standard polymerase chain reaction (PCR)-based assay and retested for comparison with a new highly sensitive transcription-mediated amplification (TMA)-based assay. Generally, in patients with virologic non-response or sustained virologic response (SR), no differences were observed between PCR- and TMA-based assays. In patients with relapse after standard interferon-alpha therapy with or without ribavirin, HCV RNA was detected in 33-36% of end-of-treatment samples previously negative by PCR-based assays. The lower rate of HCV RNA detected by TMA (7%) in end-of-treatment samples from patients after treatment with pegylated interferon-alpha 2a is most likely explained by the longer half-life of pegylated interferon-alpha in comparison with standard interferon-alpha. HCV RNA is detectable at the end-of-treatment by TMA in 7-36% of patients who were HCV RNA negative by reverse transcriptase (RT)-PCR-based methods. These PCR-negative/TMA-positive patients have to be considered as non-responders (NR) with a very low HCV RNA viral load. Future studies will show whether these patients benefit from prolonged antiviral therapy.
Hepacivirus↗
Hepatitis C virus nonstructural 5A protein and interferon resistance: a new model for testing the reliability of mutational analyses.
Presumably due to the capability of the hepatitis C virus (HCV) to evade the antiviral effects of alpha interferon, treatment is ineffective in more than half of chronically genotype HCV type 1 (HCV-1)-infected patients. Previous approaches to correlate the number of amino acid mutations within regions of HCV nonstructural (NS)-5A protein with virologic treatment response provided conflicting results. In the present study, we developed a new mathematical model to investigate NS5A sequences of HCV-1-infected patients. The mean number of all mutations within the complete NS5A protein was significantly higher in virologic responders compared to nonresponders (P = 0.008 and P = 0.0001 for amino acid residues predicted on the surface of the NS5A protein). Differences did not achieve statistical significance for NS5A regions that are currently assumed to be functionally relevant (e.g., the interferon sensitivity-determining region, the RNA-activated protein kinase-binding domain, etc.). Analyses of smoothed mutational frequencies showed that the number of mutations in other NS5A regions correlated with virologic response. Such a correlation was observed for both genuine and randomly generated NS5A sequences. The existence of local accumulations of mutations within genuine NS5A isolates that truly correlated with treatment response was defined by a refined test procedure. Upon considering the predicted residue accessibility, we identified the main focus of mutations correlating with treatment response to be the sequence from amino acids 2350 to 2370. Thus, evaluation of NS5A mutations in correlation with treatment response is improved by consideration of functional and predicted conformational amino acid properties. As shown by simulations with randomly generated sequences, multiple analyses of simple counts of local NS5A amino acid mutations and correlation with treatment response are insufficient. For improvement of mutational analysis, a refined specific functional data test procedure is proposed.
Adult↗