The Challenge of Prognosis and Staging for Hepatocellular Carcinoma

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140053/1/onco0023.pd

Boceprevir for untreated chronic HCV genotype 1 infection.

International audienceBACKGROUND: Peginterferon-ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies. METHODS: We conducted a double-blind study in which previously untreated adults with HCV genotype 1 infection were randomly assigned to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (the control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon-ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately. RESULTS: A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (P<0.001), and in 213 of the 311 patients (68%) in group 3 (P<0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (P=0.04), and in 29 of the 55 patients (53%) in group 3 (P=0.004). In group 2, a total of 44% of patients received peginterferon-ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively. CONCLUSIONS: The addition of boceprevir to standard therapy with peginterferon-ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir

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

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

Facteurs de risques de complications après cholangio-pancréatographie rétrograde endoscopique

NANCY1-SCD Medecine (545472101) / SudocPARIS-BIUM (751062103) / SudocNANCY1-Bib. numérique (543959902) / SudocSudocFranceF

Evaluation de deux scores de marqueurs biologiques, " Fibrotest " et " Forns Test " entre eux et par rapport à la biopsie hépatique, dans l'estimation du stade de fibrose hépatique chez des patients atteints d'hépatite C chronique (développement d'un nouveau score biologique)

Actuellement, l'hépatite C chronique est un problème majeur de Santé Publique, aussi bien en France qu'au Luxembourg. Pour juger de la nécessité d'un traitement anti-viral, il faut connaître la gravité des lésions hépatiques. Jusqu'à présent, la biopsie hépatique était l'examen de référence pour évaluer la sévérité de ces lésions. Il s'agit d'un examen invasif, non dénué de risques. Depuis une dizaine d'années, différentes équipes cherchent à mettre au point des méthodes biologiques non-invasives pour l'évaluation du stade de fibrose hépatique. Les plus utilisées sont le " Fibrotest " et le " Forns Test ". Nous avons mené une étude rétrospective incluant 133 patients atteints d'hépatite C chronique, suivis au Centre Hospitalier de Luxembourg (CHL). Le but de notre étude était de comparer le " Fibrotest " et le " Forns Test " entre eux et à la biopsie hépatique et de voir s'ils pouvaient remplacer cette dernière en pratique clinique. Un nouveau score biologique a également été mis au point : le " Luxtest ". Dans le cadre de notre étude, les performances du " Fibrotest " et du " Forns Test " sont difficiles à juger. En effet, le " Fibrotest " a une bonne certitude (VPN=86%) dans l'évaluation des fibroses non-significatives et la certitude du " Forns Test " est de 100% (VPP=100%) dans les fibroses significatives. Le " Fibrotest " ne peut éviter la biopsie hépatique qu'à 16% de nos patients ayant une fibrose non-significative. Le " Forns Test " peut l'éviter à 8% des patients présentant une fibrose significative. Le nouveau test mis au point (" Luxtest ") comporte les ASAT, les gamma-GT et l'alpha-2 macroglobuline. Il peut éviter la biopsie hépatique à 37% de notre population d'étude. Cependant, il faudrait encore une étude de validation pour le " Luxtest ". D'après nos résultats, " Fibrotest ", " Forns Test " et " Luxtest " peuvent remplacer la biopsie hépatique dans un nombre limité de cas. A l'heure actuelle, ils sont incapables de remplacer complètement la biopsie hépatique en pratique clinique.NANCY1-SCD Medecine (545472101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Carcinome hépatocellulaire et qualité de vie

La qualité de vie est un concept récent dont l'objectif principal est la prise en charge du malade dans sa globalité. Les domaines de la vie quotidienne y sont explorés de façon à offrir au patient le traitement le plus adapté. Le carcinome hepatocellualire (CHC) n'a à ce jour fait l'objet que de peu d'études. Nous avons donc comparé la qualité de vie d'une population de patients constituée de vingt-trois cas de CHC développés sur cirrhose à une population de patients présentant une pathologie cirrhotique sans greffe néoplastique. Du premier novembre 2000 au 30 avril 2001, nous avons étudié de façon prospective la qualité de vie de ces deux populations de patients appariées sur l'âge, le sexe et le score de Child-Pugh. L'âge moyen est de 65,7 +- 9,7 ans. Le baromètre santé-adulte de 1995-96 a permis également une comparaison avec la population générale. Les questionnaires Duke et QLQ-C30 ont été utilisés pour le recueil de données. La qualité de vie des deux groupes est similaire quel que soit le questionnaire utilisé ou le domaine exploré. Par contre, il existe une différence significative de qualité de vie dans le domaine physique entre la population générale et chaque groupe de l'étude; cette différence n'étant cependant pas suffisante pour créer une différence de qualité de vie globale. Ces résultats surprenants et contradictoires avec le peu d'études menées à ce jour, nous font soulever la question de l'information aux patients : est-elle suffisante ou est-elle mal intégrée au sein d'une population souvent peu compliante et peu concernée par la maladie ? Des études à plus grande échelle sont donc nécessaires pour y répondre.NANCY1-Bib. numérique (543959902) / SudocSudocFranceF

Ideal oral combinations to eradicate HCV: The role of ribavirin

International audienceCurrent all-oral interferon-free regimens offer sustained virological response (SVR) rates above 90% as well as 12-week treatment durations for the majority of patients with chronic hepatitis C virus (HCV), including treatment-naïve and -experienced patients with or without cirrhosis. There are multiple direct-acting antiviral (DAA) combinations that can be selected to optimize efficacy and safety outcomes. Each of them can be tailored according to different parameters including the use of ribarivin (RBV). For sofosbuvir (SOF)-based combinations, RBV is useful in the following situations: HCV genotype 1, treatment-experienced, cirrhotic patients, or patients with decompensated cirrhosis, and HCV genotype 3, cirrhotic patients. In these situations the addition of RBV allows to shorten the treatment to 12weeks in the majority of cases and therefore decreases the cost of the treatment. The need of RBV remains to be determined in cirrhotic patients with a SOF plus simeprevir regimen. RBV-containing regimens are recommended in all HCV genotype 1a patients who receive the 3-DAA combination: paritaprevir/r, ombitasvir, dasabuvir. Globally, the addition of RBV to the different combinations of DAA increases slightly the risk of anaemia. However severe anaemia was rare and easily manageable with RBV dose reduction without any impact on SVR. In practice, because RBV is cheap and well tolerated when combined with interferon-free regimen, it remains a useful tool to fine tune anti-HCV treatment regimens and optimize their results