Immune-based therapy is the mainstay treatment for chronic hepatitis C virus (HCV) infection but causes multiple side effects and achieves durable viral clearance in only approximately 50% of patients. Most new invest...Immune-based therapy is the mainstay treatment for chronic hepatitis C virus (HCV) infection but causes multiple side effects and achieves durable viral clearance in only approximately 50% of patients. Most new investigational anti-HCV compounds are direct-acting antivirals for which durability of response and risk of viral mutations and resistance are not yet known. Therefore, continuing discovery and development of new immune-based treatments is desirable. Toll-like receptors (TLRs) are pathogen recognition receptors that initiate the innate immune response. The responsiveness of HCV or other ongoing chronic systemic infections to treatment with a selective TLR agonist has not been reported. Isatoribine is a selective agonist of TLR7. In a proof-of-concept study, we found that once-daily 7-day treatment with intravenous isatoribine 800 mg caused a significant (P = .001) reduction of plasma HCV RNA (mean, -0.76; range, -2.85 to + 0.21 log10 units) in otherwise untreated patients (n = 12) who were chronically infected with HCV. Viral load reduction occurred in patients infected with genotype 1 as well as non-genotype 1 HCV. The reduction of viral load was correlated with induction of markers of a heightened immune antiviral state, including 2’ -, 5’ -oligoadenylate synthetase levels in whole blood. This treatment was well tolerated, with a low frequency of mild to moderate adverse events. In conclusion, systemic administration of the selective TLR7 agonist isatoribine resulted in dose-dependent changes in immunologic biomarkers and a statistically significant antiviral effect with relatively few and mild side effects.展开更多
Background/Aims: The outcome of infection with the hepatitis C virus (HCV) has been shown to be influenced by genetic host factors. The G protein β 3 subunit (GNB3) C825T polymorphism has been shown to determine immu...Background/Aims: The outcome of infection with the hepatitis C virus (HCV) has been shown to be influenced by genetic host factors. The G protein β 3 subunit (GNB3) C825T polymorphism has been shown to determine immune cell functions in vitro. We investigated the association of GNB3 genotypes with treatment response in HCV- infected patients. Methods: We genotyped 1781 HCV- free blood donors and 232 HCV- infected patients treated with interferon- alfa/ ribavirin. Sustained virologic response (SVR) was defined by undetectable HCVRNA 24 weeks after discontinuation of therapy. Non- response (NR) was defined by positive HCV- RNA at the end of at least 24 weeks of treatment. GNB3 genotypes were determined by DNA restriction enzyme analyses. Results: Genotype distribution was not significantly different in healthy controls and HCV- infected patients. Only in HCV genotype 1- infected patients a significant correlation between GNB3 CC genotype and NR could be observed (6 TT, 42 TC, 54 CC) versus SVR (11 TT, 25 TC, 19 CC) patients (P=0.004). In a logistic regression analysis including biochemical and virologic characteristics, only GNB3 CC genotype was significantly associated with NR (OR 4.9; 95% CI=1.4- 16.5; P=0.011). Conclusions: The GNB3 825 CC genotype is associated with NR in HCV- 1- infected patients.展开更多
Background& Aims: Standard therapy of patients with chronic hepatitis C virus (HCV) infected with HCV genotype-2 or -3 is the combination of pegylated interferon-α and ribavirin for 24 weeks. Whether shorter trea...Background& Aims: Standard therapy of patients with chronic hepatitis C virus (HCV) infected with HCV genotype-2 or -3 is the combination of pegylated interferon-α and ribavirin for 24 weeks. Whether shorter treatment durations are possible for these patients without compromising sustained virologic response rates is unknown. Methods: Patients chronically infected with HCV-2 (n = 39), HCV-2/3 (n = 1), or HCV-3 (n = 113) were treated with peginterferon-α -2a (180 μ g/wk) plus ribavirin 800- 1200 mg/day. HCV RNA was quantitatively assessed after 4 weeks. Patients with a rapid virologic response (HCV RNA below 600 IU/mL) were randomized for a total treatment duration of 16 (group A) or 24 weeks (group B). All patientswith HCV RNA ≥ 600 IU/mL at week 4 (groupC) were treated for 24 weeks. End-of-treatment and sustained virologic response were assessed by qualitative RT-PCR (sensitivity 50 IU/mL). Results: Only 11 of 153 patients (7% ) were allocated to group C. End-of-treatment and sustained virologic response rates were 94% and 82% , (group A), 85% and 80% (group B), and 73% and 36% (group C), respectively. In patients infected with genotype HCV-3 and high viral load (>800,000 IU/mL), a significant lower sustained virologic response rate was found than in patients infected with HCV-3 and a viral load lower or equal to 800,000 IU/mL (59% vs 85% , respectively; P = .003). Conclusions: In HCV-2 and -3 (low viral load)-infected patients who have a rapid virologic response, treatment for 16 weeks with peginterferon-α -2a and ribavirin is sufficient. In patients infected by HCV-3 (high viral load), longer treatment may be necessary.展开更多
Aim of our study was to analyze fibrosis progression after liver transplantation (OLT) in hepatitis C virus (HCV)-infected patients based on protocol liver biopsies and to identify risk factors, which may play a role ...Aim of our study was to analyze fibrosis progression after liver transplantation (OLT) in hepatitis C virus (HCV)-infected patients based on protocol liver biopsies and to identify risk factors, which may play a role in the development of severe fibrosis stages. One hundred and eighty-three liver graft recipients who had a histological follow-up evaluation of 1 year after OLT were analyzed. Overall 1039 protocol liver biopsies were performed after 1-, 3-, 5-, 7-and 10 years and staged according to the Scheuer score. The fibrosis progression rate was not linear. The fibrosis scores were 1.2 after one, 1.7 after three, 1.9 after five, 2.1 after 7 and 2.2 after 10 years. The 39 recipients with fibrosis stages 3 or 4 in the 1-year biopsy had a significantly reduced survival rate, while fibrosis stage 0-2 indicated excellent survival. Independent risk factors for progression of fibrosis at 1 year were HCV genotype 1 and 4 (P=0.01) and donor age > 33 years (P=0.01), whereas risk factors for development of cirrhosis (30/183 recipients (16%)) were donor age (P=0.002) and multiple steroid pulses (P=0.05). These data provide information on the course of recurrent hepatitis C and may be helpful to individualize the treatment of transplanted patients.展开更多
文摘Immune-based therapy is the mainstay treatment for chronic hepatitis C virus (HCV) infection but causes multiple side effects and achieves durable viral clearance in only approximately 50% of patients. Most new investigational anti-HCV compounds are direct-acting antivirals for which durability of response and risk of viral mutations and resistance are not yet known. Therefore, continuing discovery and development of new immune-based treatments is desirable. Toll-like receptors (TLRs) are pathogen recognition receptors that initiate the innate immune response. The responsiveness of HCV or other ongoing chronic systemic infections to treatment with a selective TLR agonist has not been reported. Isatoribine is a selective agonist of TLR7. In a proof-of-concept study, we found that once-daily 7-day treatment with intravenous isatoribine 800 mg caused a significant (P = .001) reduction of plasma HCV RNA (mean, -0.76; range, -2.85 to + 0.21 log10 units) in otherwise untreated patients (n = 12) who were chronically infected with HCV. Viral load reduction occurred in patients infected with genotype 1 as well as non-genotype 1 HCV. The reduction of viral load was correlated with induction of markers of a heightened immune antiviral state, including 2’ -, 5’ -oligoadenylate synthetase levels in whole blood. This treatment was well tolerated, with a low frequency of mild to moderate adverse events. In conclusion, systemic administration of the selective TLR7 agonist isatoribine resulted in dose-dependent changes in immunologic biomarkers and a statistically significant antiviral effect with relatively few and mild side effects.
文摘Background/Aims: The outcome of infection with the hepatitis C virus (HCV) has been shown to be influenced by genetic host factors. The G protein β 3 subunit (GNB3) C825T polymorphism has been shown to determine immune cell functions in vitro. We investigated the association of GNB3 genotypes with treatment response in HCV- infected patients. Methods: We genotyped 1781 HCV- free blood donors and 232 HCV- infected patients treated with interferon- alfa/ ribavirin. Sustained virologic response (SVR) was defined by undetectable HCVRNA 24 weeks after discontinuation of therapy. Non- response (NR) was defined by positive HCV- RNA at the end of at least 24 weeks of treatment. GNB3 genotypes were determined by DNA restriction enzyme analyses. Results: Genotype distribution was not significantly different in healthy controls and HCV- infected patients. Only in HCV genotype 1- infected patients a significant correlation between GNB3 CC genotype and NR could be observed (6 TT, 42 TC, 54 CC) versus SVR (11 TT, 25 TC, 19 CC) patients (P=0.004). In a logistic regression analysis including biochemical and virologic characteristics, only GNB3 CC genotype was significantly associated with NR (OR 4.9; 95% CI=1.4- 16.5; P=0.011). Conclusions: The GNB3 825 CC genotype is associated with NR in HCV- 1- infected patients.
文摘Background& Aims: Standard therapy of patients with chronic hepatitis C virus (HCV) infected with HCV genotype-2 or -3 is the combination of pegylated interferon-α and ribavirin for 24 weeks. Whether shorter treatment durations are possible for these patients without compromising sustained virologic response rates is unknown. Methods: Patients chronically infected with HCV-2 (n = 39), HCV-2/3 (n = 1), or HCV-3 (n = 113) were treated with peginterferon-α -2a (180 μ g/wk) plus ribavirin 800- 1200 mg/day. HCV RNA was quantitatively assessed after 4 weeks. Patients with a rapid virologic response (HCV RNA below 600 IU/mL) were randomized for a total treatment duration of 16 (group A) or 24 weeks (group B). All patientswith HCV RNA ≥ 600 IU/mL at week 4 (groupC) were treated for 24 weeks. End-of-treatment and sustained virologic response were assessed by qualitative RT-PCR (sensitivity 50 IU/mL). Results: Only 11 of 153 patients (7% ) were allocated to group C. End-of-treatment and sustained virologic response rates were 94% and 82% , (group A), 85% and 80% (group B), and 73% and 36% (group C), respectively. In patients infected with genotype HCV-3 and high viral load (>800,000 IU/mL), a significant lower sustained virologic response rate was found than in patients infected with HCV-3 and a viral load lower or equal to 800,000 IU/mL (59% vs 85% , respectively; P = .003). Conclusions: In HCV-2 and -3 (low viral load)-infected patients who have a rapid virologic response, treatment for 16 weeks with peginterferon-α -2a and ribavirin is sufficient. In patients infected by HCV-3 (high viral load), longer treatment may be necessary.
文摘Aim of our study was to analyze fibrosis progression after liver transplantation (OLT) in hepatitis C virus (HCV)-infected patients based on protocol liver biopsies and to identify risk factors, which may play a role in the development of severe fibrosis stages. One hundred and eighty-three liver graft recipients who had a histological follow-up evaluation of 1 year after OLT were analyzed. Overall 1039 protocol liver biopsies were performed after 1-, 3-, 5-, 7-and 10 years and staged according to the Scheuer score. The fibrosis progression rate was not linear. The fibrosis scores were 1.2 after one, 1.7 after three, 1.9 after five, 2.1 after 7 and 2.2 after 10 years. The 39 recipients with fibrosis stages 3 or 4 in the 1-year biopsy had a significantly reduced survival rate, while fibrosis stage 0-2 indicated excellent survival. Independent risk factors for progression of fibrosis at 1 year were HCV genotype 1 and 4 (P=0.01) and donor age > 33 years (P=0.01), whereas risk factors for development of cirrhosis (30/183 recipients (16%)) were donor age (P=0.002) and multiple steroid pulses (P=0.05). These data provide information on the course of recurrent hepatitis C and may be helpful to individualize the treatment of transplanted patients.
