IFI35, mir-99a and HCV Genotype to Predict Sustained Virological Response to Pegylated-Interferon Plus Ribavirin in Chronic Hepatitis C

International audienceAlthough, the treatment of chronic hepatitis C (CHC) greatly improved with the use of direct antiviral agents, pegylated-interferon (PEG-IFN) plus ribavirin remains an option for many patients, worldwide. The intra-hepatic level of expression of interferon stimulated genes (ISGs) and the rs12979860 CC genotype located within IFNL3 have been associated with sustained virological response (SVR), in patients with CHC. The aim of the study was to identify micro-RNAs associated with SVR and to build an accurate signature to predict SVR. Pre-treatment liver biopsies from 111 patients, treated with PEG-IFN plus ribavirin, were studied. Fifty-seven patients had SVR, 36 non-response (NR) and 18 relapse (RR). The expression of 851 human miRNAs and 30 selected mRNAs, including ISGs, was assessed by RT-qPCR. In the first group of patients (screen), 20 miRNAs out of the 851 studied were deregulated between NRs and SVRs. From the 4 miRNAs validated (mir-23a, mir-181a*, mir-217 and mir-99a), in the second group of patients (validation), 3 (mir-23a, mir-181a* and mir-99a) were down-regulated in NRs as compared to SVRs. The ISGs, studied, were accumulated in SVRs and IFNL3 rs12979860 CT/TT carriers compared respectively to NRs and CC carriers. Combining, clinical data together with the expression of selected genes and micro-RNAs, we identified a signature (IFI35, mir-99a and HCV genotype) to predict SVR (AUC:0.876) with a positive predictive value of 86.54% with high sensibility (80%) and specificity (80.4%). This signature may help to characterize patients with low chance to respond to PEG-IFN/ribavirin and to elucidate mechanisms of NR

Hepatitis B surface antigen quantification: Why and how to use it in 2011 – A core group report

Quantitative HBsAg had been suggested to be helpful in management of HBV, but assays were cumbersome. The recent availability of commercial quantitative assays has restarted the interest in quantitative serum hepatitis B surface antigen (HBsAg) as a biomarker for prognosis and treatment response in chronic hepatitis B. HBsAg level reflects the transcriptional activity of cccDNA rather than the absolute amount of cccDNA copies. Serum HBsAg level tends to be higher in hepatitis B e antigen (HBeAg)-positive than HBeAg-negative patients. Among patients with a low HBV DNA (<2000IU/ml), HBsAg <1000IU/ml in genotype D HBV infection and HBsAg <100IU/ml in genotype B/C HBV infection is associated with inactive carrier state in HBeAg-negative patients. The HBsAg reduction by nucleos(t)ide analogues (NA) is not as pronounced as by interferon treatment. On peginterferon treatment, sustained responders tend to show greater HBsAg decline than the non-responders. The optimal on-treatment HBsAg cutoff to predict response needs further evaluation in HBeAg-positive patients, but an absence of HBsAg decline together with a <2 log reduction in HBV DNA at week 12 can serve as stopping rule in HBeAg-negative patients with genotype D HBV infection. A rapid serum HBsAg decline during NA therapy may identify patients who will clear HBsAg in the long-term. There are early reports among Asian patients that an HBsAg level of <100IU/ml might predict lower risk of relapse after stopping NA treatment. In clinical practice, serum HBsAg level should be used together with, but not as a substitute for, HBV DNA

Using Pharmacokinetic and Viral Kinetic Modeling To Estimate the Antiviral Effectiveness of Telaprevir, Boceprevir, and Pegylated Interferon during Triple Therapy in Treatment-Experienced Hepatitis C Virus-Infected Cirrhotic Patients.: Effectiveness of triple therapy in cirrhotic patients

International audienceTriple therapy combining a protease inhibitor (PI) (telaprevir or boceprevir), pegylated interferon (PEG-IFN), and ribavirin (RBV) has dramatically increased the chance of eradicating hepatitis C virus (HCV). However, the efficacy of this treatment remains suboptimal in cirrhotic treatment-experienced patients. Here, we aimed to better understand the origin of this impaired response by estimating the antiviral effectiveness of each drug. Fifteen HCV genotype 1-infected patients with compensated cirrhosis, who were nonresponders to prior PEG-IFN/RBV therapy, were enrolled in a nonrandomized study. HCV RNA and concentrations of PIs, PEG-IFN, and RBV were frequently assessed in the first 12 weeks of treatment and were analyzed using a pharmacokinetic/viral kinetic model. The two PIs achieved similar levels of molar concentrations (P = 0.5), but there was a significant difference in the 50% effective concentrations (EC50) (P = 0.008), leading to greater effectiveness for telaprevir than for boceprevir in blocking viral production (99.8% versus 99.0%, respectively, P = 0.002). In all patients, the antiviral effectiveness of PEG-IFN was modest (43.4%), and there was no significant contribution of RBV exposure to the total antiviral effectiveness. The second phase of viral decline, which is attributed to the loss rate of infected cells, was slow (0.19 day(-1)) and was higher in patients who subsequently eradicated HCV (P = 0.03). The two PIs achieved high levels of antiviral effectiveness. However, the suboptimal antiviral effectiveness of PEG-IFN/RBV and the low loss of infected cells suggest that a longer treatment duration might be needed in cirrhotic treatment-experienced patients and that a future IFN-free regimen may be particularly beneficial in these patients

The Usefulness of Defining Rapid Virological Response by a Very Sensitive Assay (TMA) during Treatment of HCV Genotype 2/3 Infection

The aim of this study was to determine in patients with HCV genotype 2 or 3 the performance at week 4 of two assays with different sensitivities for HCV RNA detection, for the prediction of SVR and stratification for treatment duration (14 and 24 weeks). Recruitment was from two trials comparing 14 and 24 weeks treatment to patients with rapid virological response (RVR) (n = 550). RVR was originally defined as HCV RNA <50 IU/ml at week 4. Patients with an available frozen plasma sample drawn at week 4 and with follow-up data week 24 post-treatment were included (n = 429). HCV-RNA was prospectively measured with COBAS Amplicor V2, Roche (CA) (lower detection limit 50 IU/ml) and retrospectively assessed with VERSANT HCV-RNA Qualitative Assay, Siemens (TMA) (lower limit detection 10 IU/ml). Genotype 3 was present in 80% and genotype 2 in 20%. A SVR was achieved in 82%. At week 4 HCV-RNA was undetectable in 74.8% and 63% of serum samples tested with CA and TMA, respectively. CA undetectable/TMA positive was observed in 61/341 (18%) of the samples. In genotype 3 patients a relapse was seen in 9% of the patients with both CA and TMA undetectable and in 25% of the patients who were CA undetectable/TMA positive (p = 0.006). In patients allocated to 14 weeks treatment a relapse was observed in 11% of TMA undetectable patients and 26% of TMA positive (p = 0.031). In genotype 2 patients treated for 14 weeks relapse was observed in 6% of the patients with both CA and TMA undetectable week 4. Assays with high sensitivity for HCV RNA identifies patients at week 4 with high risk of virological relapse. We recommend that patients with genotype 3 and detectable HCV RNA at levels below 50 IU/ml do not receive truncated therapy with pegIFN and ribavirin

Impact of ribavirin dose on retreatment of chronic hepatitis C patients

AIM: To study the efficacy and factors associated with a sustained virological response (SVR) in chronic hepatitis C (CHC) relapsing patients

Selection of patients.

<p>Patients were recruited from two trials assessing shortened treatment to patients with genotype 2 or 3 and rapid virological response (<50 IU/ml week 4). In the present analysis those with RVR, not lost to follow-up and with available week 4 plasma samples were included.</p

Relapse rates according to treatment duration and TMA result week 4 (black = negative and white = positive) in patients with genotype 3 with a negative CA week 4 and allocated to either 14 or 24 weeks of treatment with pegylated interferon alfa and ribavirin.

<p>Relapse rates according to treatment duration and TMA result week 4 (black = negative and white = positive) in patients with genotype 3 with a negative CA week 4 and allocated to either 14 or 24 weeks of treatment with pegylated interferon alfa and ribavirin.</p

Relapse rates in patients with genotype 3 according to the combined result of the TMA and the CA tests at week 4.

<p>Patients with a negative CA test week 4 have been allocated to14 or 24 weeks while all patients with a positive CA have been treated for 24 weeks.</p