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Summary: Background: Limited data exist regarding tenofovir disoproxil fumarate (TDF) safety and effectiveness in chronic hepatitis B virus–infected (CHB) patients with renal impairment (RI). Aims: To compare real‐world data on renal safety and effectiveness of TDF vs entecavir (ETV) in CHB patients with moderate‐to‐severe RI. Methods: Retrospective, non‐interventional, cohort study analysing medical records for TDF/ETV‐treated CHB patients (54 European centres). Included patients experienced moderate‐to‐severe RI (creatinine clearance 20‐60 mL/min [Cockcroft‐Gault]) either before TDF/ETV initiation ('before' subgroup [baseline = treatment initiation]) or after TDF/ETV initiation ('after' subgroup [baseline = first RI occurrence]). The primary objective was TDF safety, particularly renal‐related adverse events of special interest (AESI). TDF and ETV safety and effectiveness were compared and multivariate analyses were performed using inverse probability treatment weighting. Results: 'Before' subgroup included 107 TDF‐ and 91 ETV‐treated patients; 'after' subgroup included 212 TDF‐ and 77 ETV‐treated patients. Mean baseline creatinine clearance was higher for TDF‐ vs ETV‐treated patients (both subgroups). Median follow‐up was 3.1 years (both treatments). AESI were more frequent with TDF vs ETV ('before': 18.7% vs 8.8%; 'after': 9.9% vs 3.9%); however, differences were not significant by multivariate analysis. Only TDF‐treated patients experienced renal tubular dysfunction (6.5% 'before'; 1.9% 'after') as well as renal adverse events leading to treatment discontinuation (8.4% 'before'; 7.1% 'after'). Effectiveness was similar between treatments. Conclusions: Overall safety was similar for TDF vs ETV (both subgroups). Given that renal tubular dysfunction occurred with TDF and not with ETV, renal safety concerns may be greater with TDF in CHB patients with RI. [ABSTRACT FROM AUTHOR]

Faldaprevir, a hepatitis C virus ( HCV) NS3/4A protease inhibitor, was evaluated in HCV genotype 1-infected patients who failed peginterferon and ribavirin (Peg IFN/ RBV) treatment during one of three prior faldaprevir trials. Patients who received placebo plus Peg IFN/ RBV and had virological failure during a prior trial were enrolled and treated in two cohorts: prior relapsers ( n = 43) and prior nonresponders (null responders, partial responders and patients with breakthrough; n = 75). Both cohorts received faldaprevir 240 mg once daily plus Peg IFN/ RBV for 24 weeks. Prior relapsers with early treatment success ( ETS; HCV RNA <25 IU/mL detectable or undetectable at week 4 and <25 IU/mL undetectable at week 8) stopped treatment at week 24. Others received Peg IFN/ RBV through week 48. The primary efficacy endpoint was sustained virological response ( HCV RNA <25 IU/mL undetectable) 12 weeks post treatment ( SVR12). More prior nonresponders than prior relapsers had baseline HCV RNA ≥800 000 IU/mL (80% vs 58%) and a non- CC IL28B genotype (91% vs 70%). Rates of SVR12 (95% CI) were 95.3% (89.1, 100.0) among prior relapsers and 54.7% (43.4, 65.9) among prior nonresponders; corresponding ETS rates were 97.7% and 65.3%. Adverse events led to faldaprevir discontinuations in 3% of patients. The most common Division of AIDS Grade ≥2 adverse events were anaemia (13%), nausea (10%) and hyperbilirubinaemia (9%). In conclusion, faldaprevir plus Peg IFN/ RBV achieved clinically meaningful SVR12 rates in patients who failed Peg IFN/ RBV in a prior trial, with response rates higher among prior relapsers than among prior nonresponders. The adverse event profile was consistent with the known safety profile of faldaprevir. [ABSTRACT FROM AUTHOR]

Background Insulin resistance (IR), the major feature of the metabolic syndrome, is also common in patients with chronic HCV infection. Liver fibrosis and steatosis are known potential outcome of chronic hepatitis B or C infection. Studies have shown that HIV positive individuals co-infected with HCV have more rapid live disease progression than those with HIV alone. Few data have reported the influence of IR on steatosis and fibrosis in the context of HIV-HCV coinfection. Aim To test the association among insulin resistance (IR), liver fibrosis and liver steatosis in HIV–HCV and HCV-infected patients. Patients and methods A total of 170 HIV–HCV-infected patients matched by age, gender and genotype with 170 HCV mono-infected patients were included. Patients were considered to be IR when the homeostasis model assessment of IR >2. Significant fibrosis was considered if METAVIR ≥F2 and significant steatosis if ≥10%. Results Insulin resistance was independently associated in HCV patients with fibrosis [odds ratio (OR) = 2.04 (95% CI 1.02–4)], a body mass index (BMI) >25 kg/m² [OR = 3.33 (1.47–7.69)] and steatosis [OR = 3.33 (1.67–6.67)]. Fibrosis ≥F2 was associated in HCV patients with high liver activity grade (≥A2) [OR = 8.33 (3.85–16.67)], male gender [OR = 3.03 (1.33–7.14)] and IR [OR = 2.44 (1.15–5)]. In HIV–HCV patients, ≥A2 [OR = 5.56 (1.64–20)] was associated with fibrosis. Steatosis ≥10% was associated in HCV patients with IR [OR = 3.13 (1.59–6.25) and ≥F2 (OR = 2.22 (1.15–4.17)]. In HIV–HCV, a BMI >25 kg/m² [OR = 3.85 (1.64–9.10)], ≥A2 [OR = 2.16 (1.02–4.55); P = 0.044] and nucleoside reverse transcriptase inhibitor [OR = 3.61 (1.19–10.96); P = 0.023] were independently associated with significant liver steatosis. Conclusions Insulin resistance is associated with liver fibrosis and steatosis in HCV mono-infected, but not in HIV–HCV co-infected patients. Significant liver fibrosis is associated with IR independent of liver steatosis only in HCV mono-infected patients. [ABSTRACT FROM AUTHOR]

Background Few data are available on the incidence, risk factors and contamination pathways involved in acute indigenous hepatitis E in developed countries. Aims To draw up an overall picture of hepatitis E cases, to confirm whether or not the majority of the cases were indigenous and to attempt to identify the risk factors and contamination pathways involved in hepatitis E. Methods This study was performed in the framework of a national network (ANGH) including 96 participating centres. The 19 centres with at least one case of acute HEV reported a total number of 53 cases. Results A decreasing South-to-North geographic gradient was observed. A nonspecific clinical profile was observed in many cases. Acute hepatitis E was of indigenous origin in 90% of the patients. The most relevant and/or frequent possible risk factors among the 47 indigenous metropolitan cases were water consumption from a personal water supply, uncooked shellfish consumption and the recent acquisition of a pet pig. Conclusions This national survey confirmed that acute indigenous hepatitis E is an emerging disease in developed countries such as France, and suggests that various risk factors are responsible for acute indigenous hepatitis E contamination in non-endemic countries. [ABSTRACT FROM AUTHOR]

Hepatitis C virus genotype 4 (HCV-4) infection is progressing in Europe, where epidemiology and sustained virological response (SVR) seem to be different than in the Middle East. We analysed epidemiological features and SVR rates in a retrospective study of 1532 HCV-4-infected patients, including 1056 patients infected in France, 227 immigrants infected in Egypt and 249 in sub-Saharan Africa. SVR rates were assessed in 242 naive patients of the 1532, who received peginterferon plus ribavirin for 48 weeks. HCV subtype 4a or 4d was the most common among patients infected in France, where the predominant route of transmission was intravenous drug abuse. The 4a subtype was largely predominant (93%) among patients infected in Egypt, where transmission was mostly because of parenteral treatment for schistosomiasis. More than seven different subtypes and no predominant route of infection were found in patients infected in sub-Saharan Africa. Liver fibrosis was significantly less severe in patients infected in France and Africa than in patients infected in Egypt. SVR rates were higher in patients infected in Egypt, compared with those infected in France or Africa (54.9%, 40.3% and 32.4%, respectively, P < 0.05). An overall better response was observed in patients infected with the 4a subtype. In multivariate analysis, two factors were associated independently with SVR: the Egyptian origin of transmission and the absence of severe fibrosis. In conclusion, the distribution of HCV-4 subtypes varies with the geographical origin of transmission and affects the SVR following antiviral treatment. [ABSTRACT FROM AUTHOR]

Background The area under the receiver operating characteristic (ROC) curve is widely used as an estimate of the diagnostic value for fibrosis markers. Biopsy length and fragmentation are known as risk factors of false positive or false negative of biopsy but their quantitative impact on area under the receiver operating characteristic curve variability has not been assessed. Aim To assess these relationships to better compare the fibrosis markers. Methods The area under the ROC curves of FibroTest for the diagnosis of fibrosis was estimated in patients with chronic hepatitis C using an integrated database including 1312 patients with FibroTest and biopsy. To take into account the biopsy length, we used two adjustment factors: one in which an observed area under the ROC curve could be adjusted according to the relative area under the receiver operating characteristic curve of a biopsy of a given length vs. the entire liver and one taking into account the prevalence of each fibrosis stage defining advanced and non-advanced fibrosis. Results The mean biopsy length was smaller for cirrhosis (F4, 16 mm) vs. F3, (18 mm, P = 0.01) and F0 (19 mm, P = 0.01). The mean number of fragments was higher for cirrhosis (F4 = 4.1 fragments) vs. all the other stages (F0 = 1.9, F1 = 1.9, F2 = 1.9, F3 = 2.3; P < 0.001 vs. F4). The FibroTest area under the ROC curves for the diagnosis of advanced fibrosis, adjusted for stages’ prevalence, ranged from 0.80 to 0.98 depending on biopsy length and fragmentation, respectively. Conclusion The comparison of the area under the ROC curves of fibrosis markers should take into account the biopsy length and fragmentation. [ABSTRACT FROM AUTHOR]

Aim To assess the rate of sustained virological response in naïve hepatitis C virus-type 5 patients treated by standard interferon or percutaneous endoscopic gastrostomy-interferon (peg-interferon) and ribavirin combination for 48 weeks. Patients and methods A total of 87 hepatitis C virus patients were included from 12 centres in France; 28 patients received interferon plus ribavirin and 59 were treated with peg-interferon plus ribavirin. Results Baseline characteristics were: mean age 58 ± 11 years, sex ratio 1, 66% had metavir fibrosis score ≥F2, 21% were cirrhotics and 53% had pretherapeutic viral load ≥800 000 IU/mL. Sustained virological response was achieved in 64% and 58% of hepatitis C virus-5 patients treated with interferon and peg-interferon, respectively (NS). In adherent patients, sustained virological response was obtained in 75% of patients. Sustained virological response in hepatitis C virus-5 patients (60%) was significantly higher than sustained virological response in hepatitis C virus-1 patients (37%) ( P = 0.0499) and not significantly different from sustained virological response in hepatitis C virus-2–3 patients (63%) ( P = 0.8098). Conclusions Combination therapy is effective in 60% of hepatitis C virus-5-infected patients. Sustained virological response seems better in hepatitis C virus-5 patients than in hepatitis C virus-1 patients, and is similar to that of hepatitis C virus-2–3 patients. More studies are needed to determine optimal duration of treatment in hepatitis C virus-5 patients. [ABSTRACT FROM AUTHOR]

The clinical significance of hepatitis B virus (HBV) genotypes is still under debate. The aims of this study were to assess the distribution of HBV genotypes in France and to identify the associations between HBV genotypes and patient demographics, severity of liver disease and HBeAg status in patients referred to tertiary care centres. This was a French, multicentre, retrospective study on 262 patients with chronic HBV infection. HBV genotypes were determined using INNO-LiPA. Liver fibrosis damage was evaluated by histological analysis of biopsy samples. Patients were mainly male (74%), of Caucasian (65%), Asian (17%) or African (18%) ethnicity and 36% were HBeAg positive. All A–G genotypes were found, the most frequent being genotypes D (27%) and A (24%), followed by E (13%) and C (12%), and B (7%). Mixed genotypes were detected in 16% of the cases. Genotype A was associated with sexual contact ( P < 0.001) and genotype D with transfusion ( P < 0.001) and HBe antibody positivity ( P = 0.03).The distribution of HBV genotypes differed with regard to the ethnicity, and may reflect migration patterns. Genotypes A and D were the most frequent in France. Genotype A was associated with HBeAg positivity and genotype D with HBe antibody positivity. In our European patients, we find no clear association between a given HBV genotype and liver disease severity. [ABSTRACT FROM AUTHOR]

Summary. Low pretreatment viral load has consistently been shown to be an independent predictor of sustained response (SR) in patients with chronic hepatitis C infection. We assessed the efficacy of interferon (IFN) plus ribavirin vs IFN alone in low viraemic patients (<2 millions copies/mL) who had relapsed to a previous course of IFN and the efficacy of 24 vs 48 week combination therapy in high viraemic patients. Two hundred and ninety-seven patients were randomly assigned to one of the four regimens after stratification on pretreatment viral load. All patients received IFN-α 2b (6 million units thrice weekly for 24 weeks and 3 million units thrice weekly for 24 weeks). Patients with low viraemia received either IFN-α 2b alone for 48 weeks (R1: 42 patients) or IFN-α 2b plus ribavirin (600 mg/day) for 24 weeks and IFN-α 2b alone for the next 24 weeks (R2: 48 patients). Patients with high viral load received either IFN-α 2b plus ribavirin for 24 weeks and then IFN-α 2b alone for the next 24 weeks (R3: 104 patients) or IFN-α 2b plus ribavirin for 48 weeks (R4: 103 patients). In low viraemic patients the rate of SR was 37.7% in group R1 and 59.6% in group R2 (P < 0.05). In high viraemic patients, the rate of SR was 44.7% in group R3 and 51.4% in group R4 (P: NS). Thirty-one patients discontinued treatment (10.4%) without difference regarding treatment regimen. In the regimen using ribavirin we found no difference in terms of SR between patients receiving a dose of ribavirin below 10.6 mg/kg/day (55%) or over 10.6 mg/kg/day (58%). Histological improvement occurred in 70.2% of patients regardless of the regimen. Logistic regression showed that genotype 2 and 3, Knodell score <6 and alanine aminotransferase pretreatment level >3 × upper limit of normal were significantly and independently correlated with SR. In low viraemic patients who relapsed to a previous IFN treatment, combination therapy using high-dose IFN and low-dose ribavirin is better than high-dose IFN alone. In high viraemic patients there was no benefit in increasing the duration of combination therapy from 24 to 48 weeks. In this study, it was found that low dose of ribavirin can be used safely and there is no effect of ribavirin dose on SR. [ABSTRACT FROM AUTHOR]

summary. Chronic hepatitis C virus (HCV) infection is frequently associated with type II mixed cryoglobulinaemia (MC), a benign lymphoproliferative disease (LPD). More recently, HCV has been implicated as a possible aetiologic factor of B-cell non-Hodgkin lymphoma (B-NHL). CD81, a B-cell surface receptor, has been proposed as a receptor for HCV binding and entry in circulating B cells. The stimulation of CD81 complex enables B cells to respond to lower concentrations of antigen and finally induces B-cell proliferation. We studied the phenotypic expression of CD81, CD19 and CD5 on circulating B cells in HCV patients LPD-positive or LPD-negative. Sixty-two patients were anti-HCV antibody positive. Among HCV positive patients, 44 were HCV RNA positive with an histologically proven chronic active hepatitis of whom 10 had a B-NHL, 14 an MC and 24 no extrahepatic manifestation. Eighteen patients were HCV RNA negative with evidence of resolved infection. A control group included 40 healthy subjects. Peripheral blood mononuclear cells (PBMC) were stained for surface expression of CD81, CD19 and CD5 using monoclonal antibodies, and were analyzed by flow cytometry. The percentage of PBMC expressing CD81, CD19 and CD5 receptors were compared between the groups by univariate analysis. Logistic regression model variables were then evaluated to correlate the presence of an LPD with HCV infection characteristics (i.e. age, gender, genotype, duration of infection, HCV RNA positivity, liver histological lesions), or phenotypic expression of CD81, CD19 and CD5 receptors on PBMC. HCV antibody-positive compared with HCV-negative subjects had a higher expression of CD19 receptor (23 ± 13 vs 13 ± 1%, P = 0.003). Among HCV RNA positive-patients, LPD+ compared with LPD– patients had a lower expression of CD81 (58 ± 28 vs 82 ± 18%, P = 0.001) and CD5 receptor (66 ± 16 vs 74 ± 13%, P = 0.04). In multivariate analysis, the expression of CD81 receptor... [ABSTRACT FROM AUTHOR]

summary. Different isolates of hepatitis C virus (HCV) show nucleotide sequence variability throughout the genome. Detection of antibodies to recombinant proteins derived from hepatitis C virus genotype 1, the prototype HCV clone HCV-PT, constitutes the main method for screening HCV infection. The influence of the genomic variability on the serological diagnosis of HCV by enzyme immunoassay remains poorly defined. The aim of this study was to assess the serological reactivity of a panel of well characterized French HCV isolates typed by sequence analysis from patients with chronic hepatitis. The 73 sera samples were tested in three third generation EIA tests and three confirmatory assays. HCV isolates were determined by RT-PCR and sequencing in NS5B region of the genome. The 73 sera were positive in the three EIA tests. The three confirmatory tests showed a weaker reactivity with NS5 protein whatever the genotype, and a lower reactivity in NS4 antigens of non-type 1 sequences, particularly for genotype 3. Even though the reactivity of the antigens differed among the HCV isolates, the 73 isolates from genotype 1–6 were reactive with the three commercial screening assays. These results demonstrate that using a single test is adequate in the routine diagnosis of HCV infection in clinical laboratory, as recommended by the last French and Europeen consensus conference. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) genotypes are distributed differently depending on geography and route of infection. We characterized the distribution of genotypes in a large cohort of patients with chronic hepatitis C in the South-east of France and evaluated the relative prevalence according to time of acquisition. One thousand, one hundred-and-eighty-three patients who were anti-HCV-positive were studied. HCV genotype distribution has changed significantly from the 1960s to 2000. The prevalence of genotype 1b decreased from 47% before 1978 to 18.8% in the 1990s while the prevalence of genotype 1a and 3a increased during the same period from 18% and 15.3% to 28.8% and 26.3%, respectively. The logistic regression model showed that genotype 1a was significantly more common in patients infected through intravenous drug injection odds ratio ((OR): 2.08, P < 0.01) and after 1990 (OR: 1.98, P < 0.05). Genotype 1b was significantly less frequent in patients infected through intravenous drug injection (OR: 0.17, P < 0.001) and has decreased since 1978 (OR: 0.27, P < 0.001). Genotype 3a was independently associated with intravenous drug injection (OR: 6.1, P < 0.001) and tattooing (OR: 8.01, P < 0.001) and was more frequent in the 1979–90 period (OR: 2.05 and 1.74, P < 0.001 and P < 0.05). Our results show a modification of HCV genotypes distribution over the last four decades due to an increase of intravenous drug use (IVDU) contamination and an evolution of HCV genotypes distribution only in IVDU population characterized by a decrease of genotype 1b, an increase of genotype 3a from 1970 to 1990 and a higher increase of genotype 1a which is currently the predominant genotype in our population. [ABSTRACT FROM AUTHOR]

Summary. Patients infected with hepatitis C virus genotype 4 (HCV-4) respond to interferon alpha (IFN) as poorly as those infected with genotype 1. However, there is no information on the viral dynamics of HCV-4. Interferon–ribavirin treatment was administered to untreated patients infected with HCV-4. Viral load was assessed with Versant 3.0. Viral dynamics parameters were estimated based on the bi-phasic model for HCV during IFN treatment. Viral kinetics of HCV-4 follow a bi-phasic decline pattern also. The mean effectiveness of IFN in blocking production of HCV-4 was a decline of 77.8% during the first day of treatment. The half-life of free virions was estimated at 3.5 h and that of infected cells from 1.9 to over 70 days. The viral dynamics parameters of HCV-4 appear similar to those of HCV-1 and slower than those of HCV-2. HCV-4 infected patients should be grouped with those with HCV-1 when therapeutic schemes are considered in relation to genotype. [ABSTRACT FROM AUTHOR]

. Worldwide, 50-70 million subjects are infected with an hepatitis C virus (HCV) genotype 2, 3, 4, 5 or 6. In these patients, the combination of PEG-INF-α and ribavirin remains the currently approved standard-of-care treatment. The identification of different potential therapeutic targets in the HCV life cycle has led to the development of both direct antiviral agents (DAAs) and reagents targeting host functions essential for viral replication. DAAs comprise so far first-generation, second-wave and second-generation NS3/4A protease inhibitors (PIs), nucleos(t)ide (NIs) and non-nucleoside inhibitors of the NS5B RNA polymerase and NS5A complex inhibitors. The main host-protein-directed antiviral agents are cyclophilin inhibitors and silibinin. Whereas the launch of first-generation PIs was a major landmark in the management of genotype 1 (GT-1)-infected patients, these drugs are inactive in most non-GT-1-infected patients. Several of these and other drugs have now reached phase II and even phase III clinical stage development. The purpose of this article is to provide an overview of the clinical results recently reported for the treatment for non-GT-1 HCV infection with a focus on the most promising new compounds and combinations. [ABSTRACT FROM AUTHOR]

Background: Conflicting results have been reported on the impact of tenofovir versus entecavir on liver-related outcomes., Aims: To explore trends in clinical outcomes in chronic hepatitis B virus (HBV)-infected patients and compare the impact of tenofovir versus entecavir on the risk of hepatocellular carcinoma (HCC), liver transplantation (LT) and mortality., Methods: We used the French National Health Insurance Databases (SNDS) to identify HBV-infected patients. We quantified the excess clinical burden from 2012 to 2021 by comparing the HBV-infected cohort with a general population cohort, using 1:1 exact matching on birth date, sex, social deprivation index and follow-up start date. The risks of mortality, HCC and LT were compared between patients treated with tenofovir and entecavir using inverse probability weighting., Results: A total of 101,740 patients were matched to the general population. From 2012 to 2021, the average annual decreases in excess mortality, incidence of HCC and LT were 3.7%, 8.0% and 11.9%, respectively (p for trend < 0.001). During the same period, the nucleos(t)ide analog (NUC) treatment coverage significantly increased, particularly after 2016 (p < 0.001). Among 14,054 treatment-naïve patients starting tenofovir (n = 7426) or entecavir (n = 6628), we observed no difference in the composite outcome of mortality, LT or HCC (HR, 1.09; 95% CI, 0.95-1.24). Tenofovir was associated with an increased risk of HCC compared with entecavir (HR, 1.31; 95% CI, 1.07-1.62)., Conclusions: Tenofovir was associated with a higher risk of HCC compared with entecavir, although no difference in the composite outcome of mortality or liver-related events was observed between the two treatments., (© 2024 John Wiley & Sons Ltd.)

Background and Aims: The safety and tolerability of bulevirtide (BLV), a novel entry inhibitor of hepatitis delta virus, were evaluated in an integrated analysis of clinical trial results from patients with chronic hepatitis delta (CHD)., Methods: Week 48 on-treatment clinical and laboratory results from two Phase 2 trials (MYR203 [NCT02888106] and MYR204 [NCT03852433]) and one Phase 3 trial (MYR301 [NCT03852719]) were pooled (N = 269). Patients were grouped as follows: BLV 2 mg (n = 64), BLV 10 mg (n = 115), pegylated interferon-alfa (n = 39) and control (n = 51). The control group consisted of patients assigned to the delayed treatment group in Study MYR301., Results: Adverse events (AEs) that occurred more frequently with BLV 2 mg and BLV 10 mg versus control included increased total bile acid levels (20% and 17% vs. 0%), injection-site reactions (16% and 20% vs. 0%), headache (16% and 17% vs. 0%), pruritus (11% and 10% vs. 0%) and eosinophilia (9% and 4% vs. 0%). Increases in total bile acid levels were observed with BLV without clear correlation with AEs, such as pruritus, eosinophilia or vitamin D deficiency. Grade 3 or 4 study drug-related AEs occurred in a higher proportion of patients receiving pegylated interferon-alfa (51%) than with BLV 2 or 10 mg (3% and 4%, respectively). There were no serious AEs related to BLV, and no patients discontinued BLV due to an AE. Neither hepatic decompensation nor death occurred., Conclusions: BLV monotherapy was safe and well tolerated through 48 weeks of treatment in patients with CHD., Trial Registration: NCT02888106, NCT03852433 and NCT03852719., (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Background: Hepatitis C virus genotype 5 (HCV-GT-5) is found mainly in South Africa. In our area in central France, the prevalence of HCV-GT-5 is 14%., Methods and Results: Here we evaluated sustained virological response at week 12 post-treatment (SVR12) in 147 HCV-GT-5 patients from 14 French university hospitals (2014-2021) treated with direct-acting antivirals (DAA) in real-life. Patients had mainly received sofosbuvir/ledipasvir ± ribavirin, sofosbuvir/velpatasvir, and glecaprevir/pibrentasvir. Overall SVR12 was 98% (144/147). Two patients experienced relapse: one was successfully retreated with the same DAAs (sofosbuvir/ledipasvir) plus ribavirin, and the other refused further DAA treatment. One patient with virological failure (sofosbuvir/velpatasvir) had received a second treatment (sofosbuvir/velpatasvir/voxilaprevir) and progressed to cure., Conclusions: HCV-GT-5 patients treated with a DAA regimen had a 99% SVR12 in intention-to-treat (including initial therapy and retreatment) and 100% SVR12 per protocol. Sofosbuvir/ledipasvir, sofosbuvir/velpatasvir, and glecaprevir/pibrentasvir show very good efficacy in real-world HCV-GT-5 patients., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Transjugular intrahepatic portosystemic shunt (TIPS) has become essential in the treatment or prevention of portal hypertension-related complications. In the early 1990s, the primary indication was refractory bleeding. It is now proposed for the treatment of ascites for the prevention of bleeding and in patients with vascular diseases of the liver. Thus, there are a growing number of patients being treated with TIPS all over the world. The broadening of indications, the involvement of multiple stakeholders, the need for an accurate selection, the positioning in relation to transplantation and the lack of standardization in pre-therapeutic assessment, in the procedure itself and in the follow-up have led the board of the French Association for the Study of the Liver to establish recommendations., (© 2024 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background and Aims: The economic impact of managing patients with hepatitis C virus (HCV) infection remains unknown. This study aimed to assess the economic burden of chronic HCV infection from a national health insurance perspective and the impact of direct-acting antivirals (DAAs) using nationwide real-world data., Methods: Patients with chronic HCV infection were identified from the French Health Insurance Claims Databases (SNDS) and matched for age and sex to the general population. Health resource utilization and reimbursements were summarized according to healthcare expenditure items from 2012 to 2021. The economic burden attributable to chronic HCV infection was evaluated over a 10-year period. Finally, the impact of DAAs was estimated using economic data derived from the SNDS., Results: A total of 145 187 patients with chronic HCV infection were identified. Among the patients eligible for DAA therapy, 81.5% had received DAA by the end of 2021. Over a 10-year period, managing patients with chronic HCV infection resulted in an additional cost of €9.71 billion (95% confidence interval [CI]: €9.66-€9.78 billion) or €9191 (95% CI: €9134-€9252) per patient per year compared to the general population. After DAA therapy, patients with chronic HCV infection had a higher economic burden than the general population, with an additional cost of €5781 (95% CI: €5540-€6028) per patient at the fifth-year post-DAA therapy., Conclusions: A significant economic burden persists among patients with HCV infection after DAA treatment. The high proportion of patients not treated with DAA therapy supports reinforcing policies for universal access., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: The risk of mortality in people with a history of injection drug use (PHID) is high, as is the prevalence of hepatitis C virus (HCV) infection. Although direct-acting antivirals (DAA) are effective in this population in terms of sustained virological response, it is not known whether PHID benefit as much as people with no history of injection drug use from DAA-related HCV cure in terms of reduced all-cause mortality., Methods: Using Cox proportional hazards models based on the ANRS CO22 Hepather cohort data (n = 9735), we identified factors associated with all-cause mortality among HCV-infected people. We tested for interaction effects between drug injection status, HCV cure and other explanatory variables., Results: DAA-related HCV cure was associated with a 66% (adjusted hazard ratio [95% confidence interval]: 0.34 [0.29-0.39]) lower risk of all-cause mortality, irrespective of drug injection status. Detrimental effects of unhealthy alcohol use on mortality were identified in PHID only., Discussion and Conclusions: DAA-related HCV cure led to comparable benefits in terms of reduced mortality in PHID and people with no history of injection drug use. Policies and strategies to enhance DAA uptake among PHID are needed to lower mortality in this population. Clinical trial registration details: ClinicalTrials.gov: NCT01953458., (© 2023 The Authors. Drug and Alcohol Review published by John Wiley & Sons Australia, Ltd on behalf of Australasian Professional Society on Alcohol and other Drugs.)

Background: Sofosbuvir, a prodrug nucleoside inhibitor of hepatitis C virus, has a predominant circulating metabolite that is renally eliminated. Whether sofosbuvir is associated with chronic kidney disease (CKD) progression is not well understood., Methods: We performed a retrospective analysis of patients with estimated glomerular filtration rate (eGFR) 30-89 mL/min/1.73 m 2 treated with sofosbuvir in 76 Phase 2/3 registrational trials. We evaluated eGFR at each study visit. Separately, we performed a retrospective analysis of an administrative claims database (IQVIA PharMetrics Plus™) to compare the risk of incident end-stage renal disease (ESRD) associated with the use of sofosbuvir or non-sofosbuvir regimens among patients with CKD using propensity score methods. Exposure, CKD status and outcomes were determined using diagnosis and medication claim codes. Cox proportional hazards methods were used to estimate ESRD risk., Results: Among 4642 trial participants with baseline stage 2 CKD (eGFR 60-89 ml/min/1.73 m 2 ) and 682 trial participants with stage 3 CKD (eGFR 30-59 ml/min/1.73 m 2 ) mean (SD) eGFR improved from baseline to 4 weeks post-treatment (+0.7 [9.3] and +2.6 [8.8] ml/min/1.73 m 2 , respectively; p < 0.001 each). In the second analysis, among 2042 patients with CKD receiving sofosbuvir-based regimens compared to 431 receiving non-sofosbuvir-based regimens, after adjusting for baseline covariates and weighting based on treatment propensity scores, there was no significant difference in risk of ESRD (adjusted HR = 0.85, 95% CI: 0.51-1.42)., Conclusions: Clinical trial participants with CKD did not experience worsening eGFR during sofosbuvir-based treatment, and sofosbuvir was not associated with an increased risk of ESRD in patients with CKD in a nationally-representative administrative claims database., (© 2022 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background and Aims: Late presentation for care of hepatitis C virus (HCV) infection - defined as having severe liver fibrosis when first consulting a specialist for HCV care - increases morbidity and mortality. Identifying the socio-behavioural correlates of late presentation is essential to improve HCV strategies to optimize HCV cascade of care. We investigated clinical and socio-behavioural correlates of late presentation for care in HCV mono-infected individuals., Methods: This study included chronic HCV mono-infected patients participating in the French national cohort ANRS CO22 HEPATHER, starting in 2012. The correlates of late presentation were estimated using a Heckman probit selection model, which takes into account the possible selection bias because of missing data in the outcome., Results: Among the 9174 study patients, 1236 had available data on liver fibrosis stage at first presentation for HCV care. Of these, 591 (47.8%) were late presenters. In a multivariable analysis adjusted for age, sex and HCV genotype, having diabetes (adjusted coefficient [95% confidence interval]: 0.55 [0.30; 0.80]), current hazardous alcohol use (0.36 [0.03; 0.69]) and current abstinence but past hazardous alcohol use (0.42 [0.19; 0.64]) (vs. current abstinence and no past hazardous use) were all independently associated with late presentation for HCV care., Conclusions: As late presentation severely affects HCV cascade of care, our findings bring important new evidence about the need to promptly identify and target people with diabetes and/or past or current hazardous alcohol use for HCV screening and treatment within the wider context of the WHO goal to eliminate HCV by 2030., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Despite universal health coverage in France, migrants face specific socioeconomic barriers that increase the likelihood of a suboptimal cascade of care for chronic hepatitis C virus (HCV) infection and impaired treatment effectiveness in this sub-population. We selected data collected from 2012 to 2018 from the ANRS CO22 HEPATHER prospective cohort study for chronic HCV participants with available data on treatment failure (defined as the presence of a detectable HCV-RNA load 12 weeks after their first DAA treatment ended). We performed multivariable Poisson regression models to test whether treatment failure rates differed significantly between HCV-infected migrants and non-migrants receiving DAA in France (cross-sectional analysis), while taking into account the former's world region of birth and other potential social vulnerability factors. Among the study population's 7,879 patients, 5,829 (74%) were non-migrants and 2,050 (26%) migrants. Median [interquartile range] age was 57 [51-65] years, 4433 (56%) were men and 369 (5%) of the entire study population had treatment failure. After multivariable adjustment, only migrants from Central Asia were at higher risk of treatment failure than non-migrants (aIRR = 2.83; 95% CI [1.72, 4.65]). Results from this large-scale study performed in France suggest a higher risk of DAA treatment failure in migrants from Central Asia than in non-migrants and confirm the overall low treatment failure rate in chronic HCV patients treated with DAA (whether migrants or not). Simplified models of care taking into account language and cultural barriers are needed to improve DAA effectiveness in migrants from Central Asia., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Interferon- and ribavirin (RBV)-free regimens can improve patient-reported outcomes (PROs) during treatment., Aim: To compare PROs during treatment with ledipasvir and sofosbuvir (LDV/SOF) to placebo and to LDV/SOF + RBV., Methods: Treatment-experienced CH-C genotype 1 patients with compensated cirrhosis (N = 154) were randomized to receive 24 weeks of LDV/SOF or 12 weeks of placebo followed by 12 weeks of LDV/SOF + RBV (the SIRIUS clinical trial). While blinded to their HCV RNA level and study treatment, patients completed PRO questionnaires (SF-36, FACIT-F, CLDQ-HCV, WPAI:SHP) at baseline, during and post-treatment., Results: Baseline PRO scores were similar between the two study arms. Patients receiving LDV/SOF showed improvement in a number of PROs (predominantly related to mental health) starting as early as 4 weeks after treatment initiation; no PRO decrement from baseline were noted, and no PRO scores were inferior to placebo (all P > 0.05). In the second 12 weeks, patients who were receiving LDV/SOF continued to improve PROs (up to +9.2% from a 100% maximum possible score, P < 0.05), while patients receiving LDV/SOF + RBV had less gains or no improvement in their PRO scores. However, regardless of the regimen, patients who successfully cleared the virus (N = 149) had significant improvement in all aspects of PROs (up to +12.2% by post-treatment week 12, up to +16.9% by week 24)., Conclusions: Treatment-experienced cirrhotic patients experience a notable improvement of their PROs during treatment with LDV/SOF. Furthermore, achieving SVR-12 is associated with significant PRO improvement, which further improves at post-treatment week 24 in this difficult to treat group of patients with chronic hepatitis C., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The standard of care (SOC) for the treatment of HCV genotype 2 (HCV-2) was pegylated interferon alpha plus ribavirin (PEG-IFN/RBV) at weight-based doses for a response-guided duration. The launches of sofosbuvir and daclatasvir in 2014 have resulted in new, better tolerated and shorter treatment. The combination of sofosbuvir and RBV for 12 weeks appears to be the new SOC in both European and American guidelines. The cost and therefore the access to this treatment remains a problem in many countries because of major economic constraints. For the few more difficult-to-treat patients, a combination of direct acting antivirals may be suitable and is being studied in ongoing trials. Because of rapidly changing treatment recommendations, the decision to treat HCV-2 patients with currently approved drugs or to wait until a better option is available in the future, must be made according to the stage of fibrosis., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: In HCV genotype 1-infected patients with HIV co-infection, tritherapy [HCV protease inhibitors (PIs) plus peg-interferon and ribavirin] has been shown to have an increased rate of sustained virological response. However, complex drug-to-drug interactions and tolerability issues remain a concern., Methods: Under the auspices of four French scientific societies of medicine, a committee was charged of establishing guidelines on the use of first-generation HCV PIs in these patients. This scientific committee based its work on preliminary results from tritherapy clinical trials in co-infected patients and, since data on these patients are still scarce, on the statements already made by the French Association for the Study of the Liver (AFEF) on the use of tritherapy in HCV mono-infected patients, written in May 2011 and updated in 2012. Each AFEF guideline concerning HCV monoinfection was examined to determine whether it could be used in the context of HIV/HCV coinfection., Results: These guidelines are addressed for the treatment of coinfected patients with various profiles, including treatment-naïve or patients with failure to previous bitherapy and mention those patients for whom tritherapy should start or those for whom it should be delayed. Preliminary results of triple therapy as well as factors associated to virological response are also discussed. Other issues include virological monitoring, clinical and virological criteria to stop therapy, practical treatment management, treatment adherence and the management of side effects and interactions with antiretroviral drugs. These guidelines were submitted for critical review to independent experts., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Treatment with first generation protease inhibitors (PIs) is a milestone in the history of HCV therapy. Triple therapy with boceprevir (BOC) improves sustained virological response (SVR) by 30% in treatment naïve genotype 1 patients and by 50-60% in relapsers, 40-45% in partial responders and 25% in null responders compared with the Pegylated Interferon (PEG-IFN) and ribavirin regimen. To optimize BOC treatment, screening and access to treatment must be improved in genotype 1 patients. To select the ideal candidate for immediate treatment with triple therapy, an individual risk/benefit ratio must be assessed. Recent data have shown that patients with compensated cirrhosis and more advanced disease may also benefit from this regimen. Moreover, in HCV patients with extrahepatic manifestations, patients with HCV recurrence after liver transplantation and HIV-HCV co-infected patients, immediate treatment with triple therapy should be discussed. There is growing evidence that triple therapy with BOC is cost-effective in genotype 1 patients. Finally, the treatment design of BOC must be optimized in relation to baseline characteristics, so that optimal stopping rules can be followed, Drug-drug interactions (DDIs) can be prevented and AEs can be accurately prevented and managed., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Of all hepatitis C virus patients, those with cirrhosis are most in need of treatment owing to increased morbidity and mortality. Treatment with pegylated interferon and ribavirin (PEG-IFN/RBV) has clearly shown the benefits of successful treatment by improving fibrosis, causing the regression of cirrhosis and reducing and preventing cirrhosis-related complications. However, the sustained virological response (SVR) is lower in patients with cirrhosis. First generation protease inhibitors (boceprevir and telaprevir) in combination with PEG-IFN/RBV are a major advancement in the treatment of both naïve and treatment-experienced genotype 1 patients. In naïve patients, the SVR rate with the triple regimen with boceprevir increased by 14% in patients with severe fibrosis or cirrhosis compared to PEG-IFN/RBV compared by 30% in patients with mild or moderate fibrosis. The SVR rate of the triple regimen with telaprevir increased by 10-30% compared to PEG-IFN/RBV in patients with severe fibrosis or cirrhosis and by nearly 30% in patients with mild or moderate fibrosis. The greatest benefits seem to be found in patients with cirrhosis who have relapsed, and is limited in prior non-responder patients. Thus, the choice of triple therapy in the latter should be considered in relation to the increase in side effects. There are no data on the efficacy of the triple regimen in patients with decompensated cirrhosis. Results in real-life settings show that patients with cirrhosis need to be carefully followed-up during treatment due to the increase in side effects that are greater than in clinical studies. Next generation DAAs and PEG-IFN/RBV appear to be more effective and have fewer side effects in patients with cirrhosis. Ultimately, an interferon-free regimen of DAAs combinations will probably provide a SVR in patients with cirrhosis and will probably be proposed in patients with more advanced or decompensated cirrhosis., (© 2012 John Wiley & Sons A/S.)

The recent marketing authorizations and hence availability of the new protease inhibitors, telaprevir and boceprevir, have profoundly changed the management of chronic hepatitis C patients. Guidelines for the use of these new drugs as part of a triple therapy, in combination with the standard therapy of peginterferon plus ribavirin, are proposed. The guidelines have been drawn up and evaluated by a meeting of the French Association for the Study of the Liver, posted online for comments, and extensively reviewed by international experts. The current published data on the various treatment strategies are reviewed. The guidelines address the majority of patient profiles including treatment-naïve patients and patients with failure of previous treatment. They recommend which patients should be treated with triple therapy and consider the results of triple therapy including the factors that are predictive of response. They consider the circumstances in which the length of triple therapy can be shortened and the advantages of a peginterferon plus ribavirin lead-in phase. Virological monitoring, stopping criteria, the evaluation of resistance to protease inhibitors, practical treatment management, treatment adherence and the management of side effects are discussed and simple guidelines proposed., (© 2012 John Wiley & Sons A/S.)

Of all hepatitis C virus (HCV) patients, those with cirrhosis are most in need of treatment because of increased morbidity and mortality. Treatment with pegylated-interferon (PEG-IFN) and ribavirin (RBV) (PR) has definitely shown the benefits of successful treatment by improving fibrosis, causing the regression of cirrhosis and reducing and preventing cirrhosis-related complications. However, the sustained virological response (SVR) is lower in patients with cirrhosis. First generation protease inhibitors (boceprevir and telaprevir) in combination with PR are a major advancement in the treatment of both naïve and treatment-experienced genotype 1 patients. In naïve patients, the SVR rate with the triple regimen with boceprevir was increased by 14% in patients with severe fibrosis or cirrhosis compared with PR. This benefit was lower than that observed in patients with mild or moderate fibrosis (30%). The SVR rate of the triple regimen with telaprevir was increased by 10-30% compared with PR in patients with severe fibrosis or cirrhosis compared with nearly 30% in patients with mild or moderate fibrosis. In treatment-experienced patients, previous relapsers have the highest increase in SVR with the triple regimen compared with PR, whatever the status of fibrosis. Previous partial or non-responder patients with cirrhosis had lower SVR rates than those without cirrhosis. However, the benefits of telaprevir and boceprevir vs PR was maintained. Previous non-responder patients with cirrhosis benefited the least from treatment. The relapse rate was always higher and side effects were more frequent in patients with cirrhosis compared with those without. First generation protease inhibitors plus PR appear to be a new step forward in the management of HCV genotype 1 patients with cirrhosis., (© 2012 John Wiley & Sons A/S.)

Background: The reliable diagnosis rate of diagnostic tests is provided by their intervals with acceptable accuracy (e.g. >/=90%) where a liver biopsy can be avoided., Aims: To evaluate the overall accuracy and improve the reliable diagnosis rates of blood tests for significant liver fibrosis., Methods: Five blood tests were compared with Metavir fibrosis (F) staging in 1056 patients with chronic hepatitis C., Results: Area under the receiver operating characteristics (F0-1 vs. F2-4) were: FibroMeter: 0.853, Fibrotest: 0.811, Fib-4: 0.799, aspartate aminotransferase to platelet ratio index (APRI): 0.786 and Hepascore: 0.784 (P<10(-3) between tests). The reliable diagnosis rates based on two traditional intervals defined by thresholds >/=90% of negative predictive values (NPV) and positive predictive values (PPV), diagnosing F0/1 and F2/3/4, respectively, were: FibroMeter: 43.5%, APRI: 19.6%, Fibrotest: 17.1%, Hepascore: 3.9%, Fib-4: 1.7% (P<10(-3)). By dividing the indeterminate interval by the diagnostic cut-off, two new intervals could be diagnosed reliably: F1/2 and F1/2/3. Accordingly, the reliable diagnosis rate was increased, e.g. FibroMeter: 75.5% (accuracy: 89.5%) with three intervals (F0/1, F1/2, F2/3/4). It was possible to further increase this rate by using the more exportable 90% sensitivity/specificity thresholds, e.g. FibroMeter: 90.2% (accuracy: 86.4%). By using the four intervals, the reliable diagnosis rate was 100% (accuracy: 89.5% with predictive value (PV) and 87.5% with sensitivity/specificity)., Conclusion: Reliable diagnosis is a diagnostic index devoted to clinical practice. Its rate can be increased by creating new intervals between diagnostic cut-off and 90% PVs or sensitivity/specificity thresholds. This increased the overall accuracy from 78.1 to 89.5% and reduced the need for a liver biopsy from 56.5 to 0% with the most accurate test.