Efficacy and Safety of Peginterferon Alfa-2a (40KD) Plus Ribavirin in Hepatitis C Patients with Advanced Fibrosis and Cirrhosis

AO Fatebenefratelli e Oftalmico, Milan, Italy.
Hepatology (Impact Factor: 11.06). 02/2010; 51(2):388-97. DOI: 10.1002/hep.23340
Source: PubMed

ABSTRACT The objective of this study is to determine the efficacy and safety of peginterferon alfa-2a (40 KD)/ribavirin in patients with advanced fibrosis. Data from 341 genotype 1/4 patients (99 with bridging fibrosis/cirrhosis) treated for 48 weeks and 1547 genotype 2/3 patients (380 with bridging fibrosis/cirrhosis) treated for 16 or 24 weeks enrolled in three randomized international studies were analyzed. Sustained virological response (SVR) rates decreased progressively from 60% in genotype 1/4 patients without advanced fibrosis to 51% in those with bridging fibrosis and 33% in those with cirrhosis (trend test P = 0.0028); and from 76% to 61% and 57%, respectively, in genotype 2/3 patients treated for 24 weeks (trend test P < 0.0001). Irrespective of genotype, patients without advanced fibrosis were more likely to have an earlier response to treatment that was associated with higher SVR rates and lower relapse rates during untreated follow-up. Among patients with or without a diagnosis of advanced fibrosis, rates of SVR and relapse were similar for patients with similar responses in the first 12 weeks. CONCLUSION: Compared with patients with less severe disease, SVR rates are significantly lower in patients with advanced fibrosis. However, irrespective of genotype and degree of fibrosis, the time to become hepatitis C virus (HCV) RNA undetectable was the strongest predictor of SVR.

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Available from: Stephanos Hadziyannis, Sep 08, 2014
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    • "Compensated liver cirrhosis is known to be a predictor of worse response to PegIFN plus RBV in HCV-monoinfected patients [18,19]. According to this, a prospective cohort study on 841 HIV/HCV coinfected patients reported lower efficacy of PegIFN plus RBV in cirrhotic patients compared to those without cirrhosis, although a substantial rate of SVR was achieved in HCV genotype 3 patients even in the presence of cirrhosis [20]. "
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    ABSTRACT: Background: HIV infection leads to a faster progression of liver disease in subjects infected with HCV, as compared with HCV mono-infected patients. Previous reports suggest that sustained virological response (SVR) rates are lower in HIV/HCV coinfection than in HCV monoinfection. We aimed to compare SVR rates of these two populations. Methods: We retrospectively analyzed clinical, biochemical and virological data of HCV and HIV/HCV infected patients with HCV genotypes 2 and 3 who started anti-HCV treatment between March 2004 and November 2012, at a single large center. Intention-to-treat (ITT) and per-protocol (PP) analysis were performed. Univariate and multivariate logistic regression analyses were performed to assess predictors of SVR. Results: 461 patients were analyzed: 307 (66.6%) males, 76 (16.5%) infected with HIV. Several differences at baseline between HCV monoinfected and HIV/HCV coinfected patients were observed. HCV monoinfected group was characterized by higher prevalence of genotype 2 (53% vs 5.3%), higher baseline HCV viral load (50% vs 35%), shorter mean duration of treatment (19 vs 41 weeks), more frequent use of peginterferon alfa-2a (84.5% vs 69.7%), lower prevalence of cirrhosis (6% vs 31.6%). Globally, SVR was achieved by 353 (76.6%) patients and 321 (83.8%) in the PP analysis. No statistically relevant differences were found in SVR rates between the two groups, either in ITT [78.2% (n = 301/385) vs 68.4% (n = 52/76), p =0.066, respectively] than in PP analysis [83.6% (n = 276/330) vs 84.9% (n = 45/53), p = 0.8]. Conclusions: Higher baseline viral loads and interruption of peginterferon and/or ribavirin were associated with a poor outcome of anti-HCV treatment while HIV infection was not related to major or minor probability to achieve SVR.
    BMC Infectious Diseases 09/2014; 14 Suppl 5(Suppl 5):S4. DOI:10.1186/1471-2334-14-S5-S4 · 2.61 Impact Factor
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    • "Since hepatocytes under physiological conditions reside in a soft environment in vivo, the regular culture on plastic surfaces has to be considered a non-physiological stiff environment, resembling fibrotic or cirrhotic conditions. It has already been shown that environmental stiffness affects interferon treatment and thereby therapeutic responses in HCV infection [47]. Here we provide evidence, that matrix stiffness modulates the response of HCV replicon cells towards therapeutically used statins. "
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    ABSTRACT: HMG-CoA-reductase-inhibitors (statins) have been shown to interfere with HCV replication in vitro. We investigated the mechanism, requirements and contribution of heme oxygenase-1(HO-1)-induction by statins to interference with HCV replication. HO-1-induction by fluva-, simva-, rosuva-, atorva- or pravastatin was correlated to HCV replication, using non-infectious replicon systems as well as the infectious cell culture system. The mechanism of HO-1-induction by statins as well as its relevance for interference with HCV replication was investigated using transient or permanent knockdown cell lines. Polyacrylamide(PAA) gels of different density degrees or the Rho-kinase-inhibitor Hydroxyfasudil were used in order to mimic matrix conditions corresponding to normal versus fibrotic liver tissue. All statins used, except pravastatin, decreased HCV replication and induced HO-1 expression, as well as interferon response in vitro. HO-1-induction was mediated by reduction of Bach1 expression and induction of the Nuclear factor (erythroid-derived 2)-like 2 (NRF2) cofactor Krueppel-like factor 2 (KLF2). Knockdown of KLF2 or HO-1 abrogated effects of statins on HCV replication. HO-1-induction and anti-viral effects of statins were more pronounced under cell culture conditions mimicking advanced stages of liver disease. Statin-mediated effects on HCV replication seem to require HO-1-induction, which is more pronounced in a microenvironment resembling fibrotic liver tissue. This implicates that certain statins might be especially useful to support HCV therapy of patients at advanced stages of liver disease.
    PLoS ONE 05/2014; 9(5):e96533. DOI:10.1371/journal.pone.0096533 · 3.23 Impact Factor
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    • "Liver cirrhosis may progress in 30% of chronic hepatitis C patients, and even hepatocellular carcinomas develop in 7–8% of cirrhotic patients annually [1,2]. Although the current standard therapy for HCV is combination of pegylated-interferon plus ribavirin (PEG-IFN/RBV), sustained virological response (SVR), defined as negativity for HCV RNA for 24 weeks after cessation of therapy, can be achieved for only 50% of chronic hepatitis patients, and for <30% of cirrhotic patients [3,4]. In addition to low efficacy, many adverse effects, especially cytopenia, are extremely detrimental to cirrhotic patients. "
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    ABSTRACT: Background IL28B and ITPA genetic variants are associated with the outcome of pegylated-interferon and ribavirin (PEG-IFN/RBV) therapy. However, the significance of these genetic variants in cirrhotic patients following splenectomy has not been determined. Methods Thirty-seven patients with HCV-induced cirrhosis who underwent laparoscopic splenectomy (Spx group) and 90 who did not (non-Spx group) were genotyped for IL28B and ITPA. The outcome or adverse effects were compared in each group. Interferon-stimulated gene 15 (ISG15) and protein kinase R expression in the spleen was measured using total RNA extracted from exenterate spleen. Results Sustained virological response (SVR) rate was higher in patients carrying IL28B major genotype following splenectomy (50% vs 27.3%) and in patients carrying minor genotype in the Spx group compared to non-Spx group (27.3% vs 3.6%, P < 0.05). Pretreatment splenic ISG expression was higher in patients carrying IL28B major. There was no difference in progression of anemia or thrombocytopenia between patients carrying each ITPA genotype in the Spx group. Although splenectomy did not increase hemoglobin (Hb) level, Hb decline tended to be greater in the non-Spx group. In contrast, splenectomy significantly increased platelet count (61.1 × 103/μl vs 168.7 × 103/μl, P < 0.01), which was maintained during the course of PEG-IFN/RBV therapy. Conclusions IL28B genetic variants correlated with response to PEG-IFN/RBV following splenectomy. Splenectomy improved SVR rate among patients carrying IL28B minor genotype and protected against anemia and thrombocytopenia during the course of PEG-IFN/RBV therapy regardless of ITPA genotype.
    BMC Gastroenterology 11/2012; 12(1):158. DOI:10.1186/1471-230X-12-158 · 2.37 Impact Factor
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