Willingness to use a drug consumption room among people who use drugs in Lyon, France, a city with no open scene of drug use (the TRABOUL survey).

BACKGROUND: Drug consumption rooms (DCRs) have been developed in cities with open drug scenes, with the aim to reduce drug-related harm. In Lyon, France's second-largest city, there is no distinct drug use area, which raised doubts regarding the need for a DCR. METHODS: We conducted a face-to-face survey of 264 people who use drugs (PWUDs), recruited in harm reduction or addiction treatment centers, in the streets or in squats. We assess their willingness to use a DCR, and we collected sociodemographic and medical features. Bivariable comparisons and analyses adjusted for sociodemographic parameters explored the association between willing to use a DCR and other variables, thus providing crude (ORs) and adjusted odds ratios (aORs) and 95% confidence intervals (95% CI). RESULTS: In total, 193 (73.1%) PWUDs accepted to participate (mean age 38.5 ± 9.3 years; 80.3% men). Among them, 64.2% declared willing to use a DCR. Being treatment-seeker (aOR 0.20, 95% CI [0.08-0.51]; p < 0.001) and not living alone (aOR 0.29; 95% CI [0.10-0.86], p = 0.025) were negatively associated with willing to use a DCR. By contrast, receiving precarity social insurance (aOR 4.12; 95% CI [1.86-9.14], p < 0.001), being seropositive for hepatitis C (aOR 3.60; 95% CI [1.20-10.84], p = 0.022), being cannabis user (aOR 2.45; 95% CI [1.01-5.99], p = 0.049), and reporting previous problems with residents (aOR 5.99; 95% CI [2.16-16.58], p < 0.001) or with the police (aOR = 4.85; 95% CI [1.43-16.39], p = 0.011) were positively associated. CONCLUSIONS: PWUDs, especially the most precarious ones, largely supported the opening of a DCR in Lyon, a city with no open drug scene.

End-ischemic hypothermic oxygenated perfusion for extended criteria donors in liver transplantation: a multicenter, randomized controlled trial-HOPExt.

BACKGROUND: Given the scarce donor supply, an increasing number of so-called marginal or extended criteria donor (ECD) organs are used for liver transplantation. These ECD liver grafts are however known to be associated with a higher rate of early allograft dysfunction and primary non-function because of a greater vulnerability to ischemia-reperfusion injury. The end-ischemic hypothermic oxygenated machine perfusion (HOPE) technique may improve outcomes of liver transplantation with ECD grafts by decreasing reperfusion injury. METHODS: HOPExt trial is a comparative open-label, multicenter, national, prospective, randomized, controlled study, in two parallel groups, using static cold storage, the gold standard procedure, as control. The trial will enroll adult patients on the transplant waiting list for liver failure or liver cirrhosis and/or liver malignancy requiring liver transplantation and receiving an ECD liver graft from a brain-dead donor. In the experimental group, ECD liver grafts will first undergo a classical static cold (4 °C) storage followed by a hypothermic oxygenated perfusion (HOPE) for a period of 1 to 4 h. The control group will consist of the classic static cold storage which is the gold standard procedure in liver transplantation. The primary objective of this trial is to study the efficacy of HOPE used before transplantation of ECD liver grafts from brain-dead donors in reducing postoperative early allograft dysfunction within the first 7 postoperative days compared to simple cold static storage. DISCUSSION: We present in this protocol all study procedures in regard to the achievement of the HOPExt trial, to prevent biased analysis of trial outcomes and improve the transparency of the trial results. Enrollment of patients in the HOPExt trial has started on September 10, 2019, and is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov NCT03929523. Registered on April 29, 2019, before the start of inclusion.

Impact on the Gut Microbiota of Intensive and Prolonged Antimicrobial Therapy in Patients With Bone and Joint Infection.

There is a growing interest in the potentially deleterious impact of antibiotics on gut microbiota. Patients with bone and joint infection (BJI) require prolonged treatment that may impact significantly the gut microbiota. We collected samples from patients with BJI at baseline, end of antibiotics (EOT), and 2 weeks after antibiotic withdrawal (follow-up, FU) in a multicenter prospective cohort in France. Microbiota composition was determined by shotgun metagenomic sequencing. Fecal markers of gut permeability and inflammation as well as multi-drug-resistant bacteria (MDRB) and Clostridioides difficile carriage were assessed at each time point. Sixty-two patients were enrolled: 27 native BJI, 14 osteosynthesis-related BJI, and 21 prosthetic joint infections (PJI). At EOT, there was a significant loss of alpha-diversity that recovered at FU in patients with native BJI and PJI, but not in patients with osteosynthesis-related BJI. At EOT, we observed an increase of Proteobacteria and Bacteroidetes that partially recovered at FU. The principal component analysis (PCoA) of the Bray-Curtis distance showed a significant change of the gut microbiota at the end of treatment compared to baseline that only partially recover at FU. Microbiota composition at FU does not differ significantly at the genus level when comparing patients treated for 6 weeks vs. those treated for 12 weeks. The use of fluoroquinolones was not associated with a lower Shannon index at the end of treatment; however, the PCoA of the Bray-Curtis distance showed a significant change at EOT, compared to baseline, that fully recovered at FU. Levels of fecal neopterin were negatively correlated with the Shannon index along with the follow-up (r 2 = 0.17; p < 0.0001). The PCoA analysis of the Bray-Curtis distance shows that patients with an elevated plasma level of C-reactive protein (≥5 mg/L) at EOT had a distinct gut microbial composition compared to others. MDRB and C. difficile acquisition at EOT and FU represented 20% (7/35) and 37.1% (13/35) of all MDRB/C. difficile-free patients at the beginning of the study, respectively. In patients with BJI, antibiotics altered the gut microbiota diversity and composition with only partial recovery, mucosal inflammation, and permeability and acquisition of MDRB carriage. Microbiome interventions should be explored in patients with BJI to address these issues.

Screening and care for alcohol use disorder in France: expectations, barriers and levers using a mixed-methods approach.

BACKGROUND: The widespread under-screening and under-treatment of alcohol use disorder (AUD) contributes to its health and socioeconomic burden. We conducted a mixed-methods (qualitative and qualitative) study in people with alcohol use disorder (PWAUD) to explore their expectations, as well as barriers and levers to AUD care. METHODS: Individuals with AUDIT > 15 (N = 179) were interviewed using computer-assisted interviews in several medical and non-medical sites (e.g., bars) (quantitative substudy). We also conducted semi-structured face-to-face interviews with 36 PWAUD (qualitative substudy). Using logistic regression, we explored factors associated with having previously received/sought care for AUD. Three major themes were identified in the qualitative textual analysis using a descending hierarchical classification. RESULTS: Not socializing with heavy drinkers (AOR [95%CI]:3.84[1.66-8.85]), regular smoking (9.72[3.91-24.15]) and feeling discriminated against (2.35[1.10-5.05]) were independent levers to having sought/received care for AUD, while being aged < 50 and employment were independent barriers. The five predominant themes in PWAUD discourses emerging from the textual analysis were: drinking context, medical care, alcohol treatment, tobacco/addiction and family. When triangulating results from the logistic regression and the textual analysis, two barriers (social drinking and difficulties with the medical care system), and two levers (family influence and tobacco addiction), emerged. CONCLUSION: These results underline the need for interventions targeting families and the social network to increase awareness about AUD and related care. Simplified and novel comprehensive care trajectories are urgently needed to reduce the clinical and public health burden of AUD.

Subclinical proximal tubulopathy in hepatitis B: The roles of nucleot(s)ide analogue treatment and the hepatitis B virus.

BACKGROUND: The recommended monitoring tools for evaluating nucleot(s)ide analogue renal toxicity, such as estimated glomerular filtration rate (eGFR) and phosphatemia, are late markers of proximal tubulopathy. Multiple early markers are available, but no consensus exists on their use. AIM: To determine the 24 mo prevalence of subclinical proximal tubulopathy (SPT), as defined with early biomarkers, in treated vs untreated hepatitis B virus (HBV)-monoinfected patients. METHODS: A prospective, non-randomized, multicenter study of HBV-monoinfected patients with a low number of renal comorbidities was conducted. The patients were separated into three groups: Naïve, starting entecavir (ETV) treatment, or starting tenofovir disoproxil (TDF) treatment. Data on the early markers of SPT, the eGFR and phosphatemia, were collected quarterly. SPT was defined as a maximal tubular reabsorption of phosphate/eGFR below 0.8 mmoL/L and/or uric acid fractional excretion above 10%. The prevalence and cumulative incidence of SPT at month 24 (M24) were calculated. Quantitative data were analyzed using analyses of variance or Kruskal-Wallis tests, whereas chi-squared or Fisher's exact tests were used to analyze qualitative data. Multivariate analyses were used to adjust for any potential confounding factors. RESULTS: Of the 196 patients analyzed, 138 (84 naïve, 28 starting ETV, and 26 starting TDF) had no SPT at inclusion. At M24, the prevalence of SPT was not statistically different between naïve and either treated group (21.1% vs 30.7%, P < 0.42 and 50.0% vs 30.7%, P = 0.32 for ETV and TDF, respectively); no patient had an eGFR lower than 50 mL/min/1.73 m² or phosphatemia less than 0.48 mmoL/L. In the multivariate analysis, no explanatory variables were identified after adjustment. The cumulative incidence of SPT over 24 mo (25.5%, 13.3%, and 52.9% in the naïve, ETV, and TDF groups, respectively) tended to be higher in the TDF group vs the naïve group (hazard ratio: 2.283, P = 0.05). SPT-free survival at M24 was 57.6%, 68.8%, and 23.5% for the naïve, ETV, and TDF groups, respectively. The median survival time without SPT, evaluated only in the TDF group, was 5.9 mo. CONCLUSION: The prevalence and incidence of SPT was higher in TDF-treated patients compared to naïve patients. SPT in the naïve population suggests that HBV can induce renal tubular toxicity.

The use of a thromboelastometry-based algorithm reduces the need for blood product transfusion during orthotopic liver transplantation: A randomised controlled study.

BACKGROUND: Orthotopic liver transplantation is associated with a risk of bleeding. Coagulation in cirrhotic patients is difficult to assess with standard coagulation tests because of rebalanced coagulation. This can be better assessed by thromboelastometry which can detect coagulation impairments more specifically in such patients. OBJECTIVES: Our first objective was to compare the number of units of blood products transfused during liver transplantation when using an algorithm based on standard coagulation tests or a thromboelastometry-guided transfusion algorithm. DESIGN: Randomised controlled trial. SETTING: Single-centre tertiary care hospital in France, from December 2014 to August 2016. PARTICIPANTS: A total of 81 adult patients undergoing orthotopic liver transplantation were studied. Patients were excluded if they had congenital coagulopathies. INTERVENTION: Transfusion management during liver transplantation was guided either by a standard coagulation test algorithm or by a thromboelastometry-guided algorithm. Transfusion, treatments and postoperative outcomes were compared between groups. MAIN OUTCOME MEASURES: Total number of transfused blood product units during the operative period (1 U is one pack of red blood cells (RBCs), fresh frozen plasma (FFP) or platelets). RESULTS: Median [interquartile range] intra-operative transfusion requirement was reduced in the thromboelastometry group (3 [2 to 4] vs. 7 [4 to 10] U, P = 0.005). FFP and tranexamic acid were administered less frequently in the thromboelastometry group (respectively 15 vs. 46.3%, P = 0.002 and 27.5 vs. 58.5%, P = 0.005), whereas fibrinogen was more often infused in the thromboelastometry group (72.5 vs. 29.3%, P < 0.001). Median transfusions of FFP (3 [2 to 6] vs. 4 [2 to 7] U, P = 0.448), RBCs (3 [2 to 5] vs. 4 [2 to 6] U, P = 0.330) and platelets (1 [1 to 2] vs. 1 [1 to 2] U, P = 0.910) were not different between groups. In the postoperative period, RBC or platelet transfusion, the need for revision surgery or occurrence of haemorrhage were not different between groups. CONCLUSION: A transfusion algorithm based on thromboelastometry assessment of coagulation reduced the total number of blood product units transfused during liver transplantation, particularly FFP administration. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02352181.

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.

Direct-acting antiviral therapy decreases hepatocellular carcinoma recurrence rate in cirrhotic patients with chronic hepatitis C.

BACKGROUND AND AIMS: Arrival of direct-acting antiviral agents against hepatitis C virus with high-sustained virological response rates and very few side effects has drastically changed the management of hepatitis C virus infection. The impact of direct-acting antiviral exposure on hepatocellular carcinoma recurrence after a first remission in patients with advanced fibrosis remains to be clarified. METHODS: 68 consecutive hepatitis C virus patients with a first hepatocellular carcinoma diagnosis and under remission, subsequently treated or not with a direct-acting antiviral combination, were included. Clinical, biological and virological data were collected at first hepatocellular carcinoma diagnosis, at remission and during the surveillance period. RESULTS: All patients were cirrhotic. Median age was 62 years and 76% of patients were male. Twenty-three patients (34%) were treated with direct-acting antivirals and 96% of them achieved sustained virological response. Median time between hepatocellular carcinoma remission and direct-acting antivirals initiation was 7.2 months (IQR: 3.6-13.5; range: 0.3-71.4) and median time between direct-acting antivirals start and hepatocellular carcinoma recurrence was 13.0 months (IQR: 9.2-19.6; range: 3.0-24.7). Recurrence rate was 1.7/100 person-months among treated patients vs 4.2/100 person-months among untreated patients (P=.008). In multivariate survival analysis, the hazard ratio for hepatocellular carcinoma recurrence after direct-acting antivirals exposure was 0.24 (95% confidence interval: 0.10-0.55; P<.001). CONCLUSIONS: Hepatocellular carcinoma recurrence rate was significantly lower among patients treated with direct-acting antivirals compared with untreated patients. Given the potential impact of our observation, large-scale prospective cohort studies are needed to confirm these results.

Efficacy and safety of boceprevir-based triple therapy in HCV cirrhotic patients awaiting liver transplantation (ANRS HC29 BOCEPRETRANSPLANT).

BACKGROUND AND AIMS: In this French multicentre, open-label study, we analyzed the efficacy, safety and patient-reported outcomes of a boceprevir-based triple therapy in HCV genotype 1 cirrhotic patients awaiting liver transplantation (LT). METHODS: Patients received PEG-IFN/ribavirin (RBV) for 48 weeks (W) and boceprevir from W4 to W48 or until LT. RESULTS: Fifty-one patients (80% males, median age: 56 years) were included. Fifty-seven percent had hepatocellular carcinoma and 43% end-stage liver disease. At enrolment, the median MELD score was 9 (range: 6-18); the Child-Pugh score was A in 65%, B in 35% and C in 2%. Therapy was discontinued because of severe adverse events (SAEs) in 39% of cases and virological inefficacy in 24%. 16% of patients had undetectable HCV RNA 24 weeks after the end of treatment (SVR24). LT was performed in 18 patients (35%). HCV RNA was undetectable in 16.6% at LT. Seven patients (14%) died and three deaths were attributed to treatment. SAEs (n=129) were observed in 84% of patients. Twenty-four percent of patients developed severe infections. Albumin<35g/L was independently associated with severe infection. Compared with baseline values, a significant decrease (P=0.02) of the physical dimension of health-related quality of life was observed between W4 and W24. The mean (95% CI) number of self-reported symptoms doubled during treatment (from 6.3 [4.8-7.7] to 11.8 [9.3-14.3]; P<0.001). CONCLUSIONS: The safety of the PEG-IFN/RBV/boceprevir combination is poor in patients awaiting LT, with a high risk of severe infection. Moreover, the limited efficacy confirms the indication for IFN-free combinations in these patients.

Efficiency and Safety of an Early Dose Adjustment of Ribavirin in Patients Infected With Hepatitis C Underexposed to the Drug and Treated With Peginterferon Ribavirin.

BACKGROUND: Ribavirin exposure after the first dose (D0AUC0-4h) >1755 mcg·h·L is predictive of sustained virological response (SVR) in patients with hepatitis C treated with peginterferon and ribavirin. The aim of this study was to test the benefit of ribavirin early dose adjustment based on this target in naïve patients infected with genotype 1. METHODS: A multicenter randomized controlled trial with two parallel groups; fixed-dose (FD) group: standard of care in 2010-2011, ie, peginterferon-α2a 180 mcg·wk and weight-based ribavirin 1000-1200 mg/d during 48 weeks; adapted-dose (AD) group: increase of ribavirin dose if D0AUC0-4h <1755 mcg·h·L. RESULTS: A total of 221 patients were included, 110 in the AD group and 111 in the FD group with similar baseline characteristics. In the perprotocol analysis, SVR was higher in the AD group (55.1% versus 40.4%; P = 0.042), especially in patients with D0AUC0-4h <1755 mcg·h·L (54.3% versus 31.9%; P = 0.029). In the intention-to-treat analysis, the difference was not significant (50% versus 41%; P = 0.197). Ribavirin trough concentrations (C0s) at week 4 of treatment (intention-to-treat analysis) were higher in patients achieving SVR (2.06 versus 1.72 mg/L, P = 0.003). In the subgroup of patients with AUC0-4h <1755 mcg·h·L, 46% of patients with AD achieved a C0 >2.0 mg/L versus 22% of patients with FD (P = 0.013). Grade 1 anemia (but not other grades) was more frequent in the AD group (70% versus 48%, P = 0.001). The number of dose reductions or discontinuation of ribavirin was similar in both groups. CONCLUSIONS: Early ribavirin dose adjustment increases SVR in patients underexposed to ribavirin without increasing grade II-IV anemia. Such a strategy could be useful in patients with no access to new antiviral drugs.

Sofosbuvir plus daclatasvir with or without ribavirin for chronic hepatitis C infection: Impact of drug concentration on viral load decay.

BACKGROUND: Sofosbuvir (SOF) plus daclatasvir (DCV) with or without ribavirin is one of the currently recommended treatment option for chronic hepatitis C. AIMS: Our objectives were to identify factors associated with SOF/DCV plasma concentrations [C] variations and to evaluate their impact on viral kinetics. METHODS: 130 consecutive HCV patients initiating SOF/DCV therapy with or without ribavirin were enrolled. Clinical, biological, virological and pharmacological data were collected at baseline, at week 4, 8, 12, and 24 of therapy and 12 weeks after the end of therapy. RESULTS: Mean age was 57 years, 68% of patients were males, 69% were infected by HCV genotype 1 and cirrhosis was observed in 76% of patients. Multivariate analysis showed that higher SOF [C] and DCV [C] during treatment were associated with eGFR impairment and absence of cirrhosis. We found a significant correlation between the magnitude of HCV viral load decrease from day 0 to week 4 and a higher SOF [C] at week 4 (p=0.032) and a higher DCV [C] at week 8 (p=0.013). CONCLUSIONS: Pharmacological monitoring showed significant associations between elevated SOF or DCV [C] and absence of cirrhosis, decreased eGFR and viral load decrease during the first month of treatment.

Increased Ribavirin Bioavailability Associated With Telaprevir Use in Hepatitis C Patients Treated With PEGylated -Interferon/Ribavirin/Telaprevir Triple Therapy.

BACKGROUND: Anemia is more frequent in patients receiving telaprevir with PEGylated interferon/ribavirin (PEG-IFN/RBV) than in those receiving PEG-IFN/RBV alone. OBJECTIVES: The objective was to measure the impact of telaprevir on RBV bioavailability and to assess the concomitant renal function. MATERIALS AND METHODS: Thirty-seven hepatitis C virus (HCV) patients non-responders to a previous course of PEG-IFN/RBV therapy and re-treated with triple therapy combining PEG-IFN/RBV and telaprevir were analyzed. RBV bioavailability was measured before the triple therapy initiation, during telaprevir treatment at week (W) 4 and W8, and after telaprevir cessation (post W16). The renal function was assessed by estimating the glomerular filtration rate (eGFR). RESULTS: At W4, RBV bioavailability, expressed as mg/L/daily dose/kg body weight, was significantly increased (median increase = 0.06 mg/L/dose/kg; P < 0.001). In parallel, the renal function was impaired with a mean eGFR decrease of -6.8 mL/minutes/1.73 m² (P = 0.109). Between W4 and W8, RBV bioavailability continued to increase (P < 0.001) but subsequently decreased slightly after telaprevir discontinuation with a concomitant restoration of the renal function (eGFR increase of 6.34 mL/minutes/1.73 m²). CONCLUSIONS: Our results indicated a reversible increase in RBV bioavailability after telaprevir exposure, which might be linked to the impairment of the GFR. This also suggests a RBV-telaprevir pharmacological interaction, a possible source of severe anemia observed under triple therapy. These results suggest that RBV pharmacological monitoring may be clinically relevant, especially in the context of first-generation HCV protease inhibitor-based therapy.

Anti-E1E2 antibodies do predict response to triple therapy in treatment-experienced Hepatitis C Virus-cirrhosis cases.

BACKGROUND AND AIMS: We previously showed that pre-treatment serum anti-E1E2 predicted hepatitis C virus (HCV) RNA viral kinetics (VKs) and treatment outcome in patients with chronic hepatitis C receiving pegylated interferon/ribavirin (Peg-IFN/RBV) double therapy. Here, we determined whether baseline anti-E1E2 was correlated with the on-treatment VK and could predict virological outcome in treatment-experienced HCV-infected cirrhotic patients receiving protease inhibitor-based triple therapy. METHODS: Sera from 19 patients with HCV genotype 1 infection and compensated cirrhosis who failed to respond to a prior course of Peg-IFN/RBV were selected at time 0 before starting triple therapy with boceprevir or telaprevir. We assessed patients with sustained viral response 12 weeks after the end of triple therapy (SVR12) by analyzing VKs at weeks 4, 12, 24, 36, 48 (end of treatment) and 60. RESULTS: Patients baseline characteristics were similar to the well-defined CUPIC cohort (age, HCV subtype, baseline viremia, and treatment history). Among the 19 patients, 11 achieved an SVR12. Fifteen patients were positive for pre-treatment anti-E1E2 and all of them achieved SVR12. Moreover, anti-E1E2 and SVR12 correlated with prior response to IFN/RBV therapy (relapse, partial or null response). CONCLUSIONS: Baseline anti-E1E2 could be considered as a new biomarker to predict SVR12 after triple therapy in this most difficult-to-treat population. These results warrant further validation on larger cohorts including patients receiving highly effective direct-acting antivirals to explore whether this test could help in better defining treatment duration for these very costly molecules.

Care of hepatitis C virus infection in France: modifications in three consecutive surveys between 1995 and 2010.

BACKGROUND & AIMS: To determine the characteristics of hepatitis C (HCV)- infected patients in 2010 and compare this survey with those reported in 1995 and 2001. PATIENTS AND METHODS: Observational multicentre study conducted in 2010 in French internal medicine, infectious diseases and hepatology departments. RESULTS: A total of 1621 HCV infected patients (mean age 50.1 ± 10.7 years; sex ratio M/F 1.8; genotype 1: 55.7%) were included. Of these, 910 (56.1%) were HIV­HCV co-infected, 463 (40.4%) were asymptomatic and 184 (16.1%) had cirrhosis at inclusion in this study. Positive viraemia was found in 1,025 patients (65.5%) at inclusion in this study. A complete pretreatment evaluation including investigation for HCV RNA, genotype determination and liver fibrosis was performed in 96.5, 80.5 and 68.7% of the 1,621 patients respectively. Previous and ongoing HCV treatments were noted in 49.6% and 20.1% of patients respectively. A sustained virological response (SVR) was observed in 271/801 (38.3%) patients, i.e. 44.1% and 30.7% in co-infected and mono-infected patients respectively. Cirrhosis was more frequent in the 2010 than in the 2001 and 1995 surveys (16.1% vs. 10.4% and 7.4% respectively; P < 0.0001). A complete pretreatment evaluation was performed in 57.9% and 50.9% of patients in 2010 and 2001 (P < 0.0001). Liver fibrosis evaluation was more frequent in 2010 than in the 2001 and 1995 surveys (68.7% vs. 62.7% and 28.7%, respectively, P < 0.0001). CONCLUSION: The care of HCV-infected patients has changed significantly in 'real life' through an improvement of pretreatment evaluation before the antiviral introduction and the increased use of antivirals. New HCV therapy combinations including protease inhibitors are warranted to increase the SVR rate.

Lower ribavirin biodisponibility in patients with HIV-HCV coinfection in comparison with HCV monoinfected patients.

BACKGROUND: In HIV infected patients, the impact of ribavirin (RBV) pharmacology on sustained virologic response (SVR) to hepatitis C virus (HCV) treatment has not been fully investigated. The objective of this study was to compare the early RBV plasma exposure between a population of HIV-HCV coinfected patients and an HCV monoinfected group. METHODS: Early RBV plasma exposure (expressed as Area Under the Curve (AUC) from 0 to 4 h) after a 600 mg first dose of RBV was measured in a population of HIV-HCV coinfected patients in comparison with an HCV monoinfected group. Peripheral blood samples were collected before the 600 mg RBV first dose (T0) to ensure no detectable baseline plasma RBV, and then 30 mn, 1, 2 and 4 hours after RBV intake (T0.5, T1, T2 and T4). RESULTS: Eighty-six patients with chronic hepatitis C entered the study among whom 23 (27%) were HIV-HCV coinfected. Coinfected patients had a significantly lower RBV-AUC(0-4h) (median: 1469 µg*h/L [range 936-3677]) compared with monoinfected patients (2030 µg*h/L [851-7700]; p = 0.018). This RBV under exposure in coinfected patients persisted after normalization of AUC to RBV dose per kilogram of body weight (182 µg*h/L [110-425] versus 271 µg*h/L [82-1091], p = 0.001). CONCLUSIONS: These results suggest that lower early bioavailability of RBV could be one of the reasons for lower SVR in HIV-HCV coinfected patients treated with pegylated interferon/RBV combination therapy. RBV plasma underexposure seems to be associated with the immunological status of the patients with lower AUC(0-4h) values observed in the more immunosuppressed coinfected patients.

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.

A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is a prevalent liver disease associated with increased morbidity and mortality. Ursodeoxycholic acid (UDCA) may have antioxidant, anti-inflammatory, and antifibrotic properties and may reduce liver injury in NASH. To date, no studies have assessed the efficacy and safety of high-dose UDCA (HD-UDCA) in patients with NASH. METHODS: We conducted a 12-month, randomized, double-blind, placebo-controlled multicenter trial to evaluate the efficacy and safety of HD-UDCA (28-35 mg/kg per day) in 126 patients with biopsy-proven NASH and elevated alanine aminotransferase (ALT) levels. The primary study end point was reduction in ALT levels from baseline in patients treated with HD-UDCA compared with placebo. Secondary study end points were the proportion of patients with ALT normalization, relative reduction in the scores of serum markers of fibrosis and hepatic inflammation, and safety and tolerability. RESULTS: HD-UDCA significantly reduced mean ALT levels -28.3% from baseline after 12 months compared with -1.6% with placebo (p<0.001). At the end of the trial, ALT levels normalized (≤35 IU/L) in 24.5% of patients treated with HD-UDCA and in 4.8% of patients who received placebo (p=0.003). Both results were not accounted for by changes in weight during the trial. HD-UDCA significantly reduced the FibroTest® serum fibrosis marker (p<0.001) compared with placebo. HD-UDCA also significantly improved markers of glycemic control and insulin resistance. There were no safety issues in this population. CONCLUSIONS: Treatment with HD-UDCA was safe, improved aminotransferase levels, serum fibrosis markers, and selected metabolic parameters. Studies with histologic end points are warranted.

Association of anti-E1E2 antibodies with spontaneous recovery or sustained viral response to therapy in patients infected with hepatitis C virus.

UNLABELLED: The monoclonal antibody (mAb) D32.10 recognizes a discontinuous epitope encompassing three regions E1 (amino acids 297-306), E2A (amino acids 480-494), and E2B (amino acids 613-621) juxtaposed on the surface of serum-derived hepatitis C virus (HCV) particles (HCVsp). The mAb D32.10 inhibits efficiently and specifically the binding of HCVsp to human hepatocytes. Therefore, we investigated the clinical relevance of anti-E1E2A,B response in the serum of patients infected with HCV. To this end, an enzyme-linked immunosorbent assay (ELISA) using synthetic E1-, E2A-, and E2B-derived peptides was used. The ELISA was validated in terms of sensitivity, specificity, and test efficiency. The detection of the anti-E1E2 D32.10 epitope-binding antibodies during natural HCV infection in more than 300 HCV-positive sera demonstrated significantly (P < 0.001) higher prevalence of these antibodies: (1) in patients who spontaneously cured HCV infection (46 of 52, 88.5%) showing high titers (70% ≥ 1/1000) compared to never-treated patients with chronic hepatitis C (7 of 50, 14%) who actively replicated the virus, and (2) in complete responders (20 of 52, 38.5%) who cleared virus following treatment and achieved a sustained viral response compared to nonresponders (4 of 40, 10%). Serum anti-E1E2 antibodies were monitored before, during, and after the current standard-of-care therapy (pegylated interferon plus ribavirin) in responder and nonresponder patients. Optimal cutoff values were assessed by receiver operating characteristic curve analysis. One month prior to therapy initiation, the threshold of 1131 (optical density × 1000) gave 100% and 86% positive and negative predictive values, respectively, for achieving or not achieving a sustained viral response. CONCLUSION: The anti-E1E2 D32.10 epitope-binding antibodies are associated with control of HCV infection and may represent a new relevant prognostic marker in serum. This unique D32.10 mAb may also have immunotherapeutic potential.