Prediction of sustained virological response by ribavirin plasma concentration at week 4 of therapy in hepatitis C virus genotype 1 patients.

BACKGROUND: Pegylated interferon/ribavirin combination is currently the standard treatment for chronic hepatitis C virus (HCV) infection. Body weight adjustment of ribavirin is crucial for response. However, previous studies found no relation between ingested dose and plasma concentration. The aim of this study was to define the ribavirin trough plasma concentration at week 4 (W4) associated with sustained virological response (SVR). METHODS: Thirty-one HCV genotype 1 patients (8 naive and 23 non-responders to a previous pegylated interferon/ribavirin therapy) were treated with pegylated interferon/ribavirin and assessed by HPLC for ribavirin plasma concentration at W4. RESULTS: Eleven patients (35%) achieved SVR, whereas 20 (65%) were non-responders. The median ribavirin plasma concentration at W4 (1.90 mg/l) varied from 1.62 mg/l in patients with subsequent non-response to 2.28 mg/l in sustained responders (P=0.007). Receiver operating characteristic curve analysis indicated that the 2.01 mg/l threshold gave the best sensitivity and specificity (73% and 80%, respectively, area under the curve =0.80; P=0.007). Sixty-seven percent of patients with median ribavirin plasma concentration >2 mg/l achieved SVR versus only 16% below this level (P=0.007). Multivariate regression analysis indicated that a ribavirin plasma concentration >2 mg/l at W4 was associated with SVR independent of gender, age, weight, baseline viral load and response to previous therapy. CONCLUSION: These results, which remain to be confirmed in large clinical trials, highlight the potential relevance of ribavirin plasma level monitoring at an early stage of treatment. This monitoring could be of help in guiding antiviral therapy by offering dose adjustment in patients with ribavirin plasma level below the 2 mg/l threshold.

Anti-E1E2 antibodies status prior therapy favors direct-acting antiviral treatment efficacy.

INTRODUCTION: Presence of anti-E1E2 antibodies was previously associated with spontaneous cure of hepatitis C virus (HCV) and predictive before treatment of a sustained virological response (SVR) to bi- or tri-therapy in naïve or experienced patients, regardless of HCV genotype. We investigated the impact of anti-E1E2 seroprevalence at baseline on treatment response in patients receiving direct-acting antiviral (DAA) therapy. MATERIAL AND METHODS: We screened anti-E1E2 antibodies by ELISA in serum samples collected at treatment initiation for two groups of patients: 59 with SVR at the end of DAA treatment and 44 relapsers after DAA treatment. Nineteen patients received a combination of ribavirin (RBV) or PEG-interferon/ribavirin with sofosbuvir or daclatasvir and others received interferon-free treatment with DAA±RBV. HCV viral load was measured at different time points during treatment in a subgroup of patients. RESULTS: A significant association was observed between presence of anti-E1E2 and HCV viral load<6log10 prior treatment. Among patients with anti-E1E2 at baseline, 70% achieved SVR whereas among patients without anti-E1E2, only 45% achieved SVR. Conversely, 66% of patients experiencing DAA-failure were anti-E1E2 negative at baseline. In the multivariate analysis, presence of anti-E1E2 was significantly associated with SVR after adjustment on potential cofounders such as age, sex, fibrosis stage, prior HCV treatment and alanine aminotransferase (ALT) level. CONCLUSIONS: The presence of anti-E1E2 at treatment initiation is a predictive factor of SVR among patients treated with DAA and more likely among patients with low initial HCV viral load (<6log10). Absence of anti-E1E2 at baseline could predict DAA-treatment failure.

Pretreatment predictive factors for hepatitis C therapy outcome: relevance of anti-E1E2 antibodies compared to IP-10 and IL28B genotypes.

BACKGROUND: Unique serum anti-E1E2 antibodies were shown to be associated with spontaneous recovery or predictive of sustained virological response (SVR) in patients with chronic hepatitis C receiving pegylated interferon/ribavirin (PEG-IFN/RBV) therapy. The objectives were to establish the relationship between pretreatment anti-E1E2 titres and HCV RNA kinetics during PEG-IFN/RBV therapy, and to examine whether the combined determination of interleukin (IL)28B rs12979860 and rs8099917, pretreatment inducible protein (IP)-10 levels and/or anti-E1E2 improved the prediction of SVR. METHODS: Sera from 26 treatment-naive consecutive HCV patients treated with PEG-IFN/RBV for 48 weeks were analysed. Serum anti-E1E2 titres and pretreatment IP-10 levels were measured by enzyme-linked immunosorbent assays. The IL28B variants were determined using genotyping real-time polymerase chain reaction method. Viral decline was measured at weeks (W) 4 and 12 and SVR assessed 6 months after the end of therapy. RESULTS: Baseline anti-E1E2 titres were correlated with HCV RNA decline at W4 and W12 and were highly predictive of SVR with 100% of patients negative for anti-E1E2 failing to achieve SVR. Receiver operating characteristic curve analyses indicate that the best prediction of SVR (AUC 0.990) was obtained with the combination of anti-E1E2 and IP-10 levels. Predictive values were better than those obtained with IP-10 alone or in combination with IL28B variants. CONCLUSIONS: Pretreatment serum anti-E1E2 response predicts HCV RNA clearance kinetics and treatment outcome. The combination of anti-E1E2 and IP-10 significantly improved the prediction of treatment response. This warrants further investigation and validation on larger cohorts of patients in the context of new therapeutic strategies.

Pharmacological exposure to ribavirin: a key player in the complex network of factors implicated in virological response and anaemia in hepatitis C treatment.

Ribavirin remains today a pivotal drug in the treatment of hepatitis C; in standard double therapy, as well as in triple combination with direct antiviral agents, ribavirin reduces relapse and can double the sustained virological response obtained with peginterferon alone or in association with direct antiviral agents. In the complex network of interacting factors determining sustained virological response independently of known predictive factors related to host and virus, two modern tools are emerging: polymorphisms in the IL28B gene and very early exposure to ribavirin. The use of a pharmacokinetic-pharmacodynamic model of early ribavirin exposure to adjust the dose individually would help promote a safer ribavirin use and improve sustained virological response. The variability of the influence of ribavirin exposure on anaemia is probably genetically determined; however, the low prevalence of the implicated protective alleles of the inosine triphosphate pyrophosphatase gene could explain their lack of influence on sustained virological response.

Amantadine triple therapy for non-responder hepatitis C patients. Clues for controversies (ANRS HC 03 BITRI).

BACKGROUND/AIMS: To determine whether addition of amantadine to pegylated interferon/ribavirin improved response rates among chronic hepatitis C patients, non-responders to interferon/ribavirin and study the dynamic of response. METHODS: In a double blind, multicenter, randomized trial, 200 non-responder patients received pegylated interferon 1.5 microg/kg per week and ribavirin 800-1200 mg/day, plus either amantadine 200 mg/day or placebo for 48 weeks. Endpoints were virological responses, ALT normalization, and histological benefit overtime. RESULTS: Twenty percent of all patients achieved a sustained virological response (SVR). This rate was 8% higher in the triple therapy group (24%) compared with the double therapy group (16%) (P = 0.22). A better virological response rate at week 24 was observed in the triple regimen group (43 vs 29%; P = 0.06), which was lost at week 48 suggesting viral escape. The biochemical response rate was also significantly higher with triple therapy at week 12 (63 vs 49%; P = 0.05) and week 24 (64 vs 49%; P = 0.03). Fibrosis stabilized or improved in 77% of all patients. CONCLUSIONS: Re-treatment of interferon/ribavirin non-responder patients should be encouraged since a substantial proportion benefits from re-treatment with pegylated interferon/ribavirin +/- amantadine. In triple therapy involving amantadine, a time wise response and an increased SVR rate in subgroups less prone to viral breakthrough suggest clues for existing controversies.

The predictive value of core antigen testing for the management of hepatitis C patients receiving pegylated interferon/ribavirin treatment.

A new quantitative marker of HCV viremia based on the detection of the core antigen of the virus has recently become commercially available in Europe. The usefulness of this test was examined for the management of patients treated with pegylated interferon/ribavirin. One hundred twenty-eight pegylated interferon/ribavirin treated patients were studied. Serum samples were available at baseline, week 4 and week 12 time-points, respectively. Core antigen was quantified using the trak-C assay (Ortho Clinical Diagnostics, Raritan, NJ). For all genotypes at week 4, the positive and negative predictive values of HCV core antigen were 81.4 and 92.9%, respectively, while at week 12 they were 67.9 and 100%, respectively. These predictive values varied substantially according to viral genotype. Among patients with a negative core antigen level (<1.5 pg/ml) at week 12, only 33% of those who were positive at week 4 achieved a sustained virological response whereas 85% of those who were already negative did (P < 0.001). The core antigen assay may be used at week 4 and week 12 to distinguish patients who will achieve a sustained virological response from those who will relapse/breakthrough. This assay is a new reliable alternative for early prediction of virological non-response in patients treated with pegylated interferon/ribavirin.