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1. Treatment with bulevirtide in HIV-infected patients with chronic hepatitis D: ANRS HD EP01 BuleDelta and compassionate cohort

Author

Victor de Lédinghen, Claire Fougerou-Leurent, Estelle Le Pabic, Stanislas Pol, Dulce Alfaiate, Karine Lacombe, Marie-Noëlle Hilleret, Caroline Lascoux-Combe, Anne Minello, Eric Billaud, Isabelle Rosa, Anne Gervais, Vlad Ratziu, Nathalie Ganne, Georges-Philippe Pageaux, Vincent Leroy, Véronique Loustaud-Ratti, Philippe Mathurin, Julie Chas, Caroline Jezequel, Sophie Métivier, Jérôme Dumortier, Jean-Pierre Arpurt, Tarik Asselah, Bruno Roche, Antonia Le Gruyer, Marc-Antoine Valantin, Caroline Scholtès, Emmanuel Gordien, Christelle Tual, Amel Kortebi, Fatoumata Coulibaly, Eric Rosenthal, Miroslava Subic-Levrero, Dominique Roulot, Fabien Zoulim, François Raffi, Laurent Alric, Patrick Miailhes, Albert Tran, Christiane Stern, Xavier Causse, Simona Tripon, Ghassan Riachi, Olivier Chazouillères, Armando Abergel, Louis d’Alteroche, Jérôme Gournay, Garance Lagadic, Patrizia Carrieri, Ségolène Brichler, Martin Siguier, Jessica Krause, Juliette Foucher, Souad Ben Ali, Magdalena Meszaros, Anne Varaut, and Valérie Canva

Subjects
Cirrhosis, HDV, HBV, Pegylated interferon, Hepatitis D, HDV RNA, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background & Aims: In France, bulevirtide (BLV) became available in September 2019 through an early access program to treat patients with HDV. The aim of this analysis was to evaluate the efficacy and safety of BLV in patients with HIV and HDV coinfection. Methods: Patients received BLV 2 mg ± pegylated interferon-α (pegIFNα) according to the physician’s decision. The primary endpoint (per-protocol analysis) was the virological response rate at Week 48, defined as the proportion of patients with undetectable serum HDV RNA or a HDV RNA decline >2 log10 IU/ml from baseline. Results: The characteristics of the 38 patients were as follows: 28 male, mean age 47.7 years, and mean baseline HDV RNA viral load 5.7 ± 1.2 log10 IU/ml. Median HIV viral load and mean CD4 count were 32 (30–65) copies/ml and 566 ± 307/mm3, respectively. Eight patients stopped treatment before Week 48. At Week 48, 10 of 19 patients (52.6%) in the 2 mg BLV group and five of seven patients (71.4%) in the 2 mg BLV + pegIFNɑ group had reached virological response (no HDV RNA available in four patients). At Week 48, seven of 19 patients in the 2 mg BLV group and three of six patients in the 2 mg BLV + pegIFNɑ group had a combined response (virological response and normal alanine aminotransferase level). Conclusions: Adults living with HIV coinfected with HDV can be treated by BLV with a virological response in more than 50% of patients. The combination of BLV and pegIFNɑ showed a strong virological response. Impact and implications: Bulevirtide is the only EMA-approved drug for HDV treatment, and we showed that it can be used in adults living with HIV, with an overall good tolerability. Bulevirtide induces a virological response in more than 50% of patients, suggesting that bulevirtide should be considered as a first-line therapy in this specific population. Bulevirtide in combination with pegIFNα could be used in patients without pegIFNα contraindication. No specific drug–drug interaction is reported. Bulevirtide is the only EMA-approved drug for HDV treatment, and we showed that it can be used in adults living with HIV, with an overall good tolerability. Bulevirtide induces a virological response in more than 50% of patients, suggesting that bulevirtide should be considered as a first-line therapy in this specific population. Bulevirtide in combination with pegIFNα could be used in patients without pegIFNα contraindication. No specific drug–drug interaction is reported. Bulevirtide is the only EMA-approved drug for HDV treatment, and we showed that it can be used in adults living with HIV, with an overall good tolerability. Bulevirtide induces a virological response in more than 50% of patients, suggesting that bulevirtide should be considered as a first-line therapy in this specific population. Bulevirtide in combination with pegIFNα could be used in patients without pegIFNα contraindication. No specific drug–drug interaction is reported.

Published
2024
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3. Broad-spectrum activity of bulevirtide against clinical isolates of HDV and recombinant pan-genotypic combinations of HBV/HDV

Author

Roberto Mateo, Simin Xu, Alex Shornikov, Tahmineh Yazdi, Yang Liu, Lindsey May, Bin Han, Dong Han, Ross Martin, Savrina Manhas, Christopher Richards, Caleb Marceau, Thomas Aeschbacher, Silvia Chang, Dmitry Manuilov, Julius Hollnberger, Stephan Urban, Tarik Asselah, Dzhamal Abdurakhmanov, Pietro Lampertico, Evguenia Maiorova, and Hongmei Mo

Subjects
hepatitis delta virus, hepatitis, Bulevirtide, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background & Aims: Bulevirtide (BLV) is a small lipopeptide agent that specifically binds to the sodium taurocholate cotransporting polypeptide (NTCP) bile salt transporter and HBV/HDV receptor on the surface of human hepatocytes and inhibits HDV and HBV entry. As a satellite virus of HBV, HDV virions are formed after assembly of HDV RNA with the HBV envelope proteins (HBsAg). Because both viruses exist as eight different genotypes, this creates a potential for high diversity in the HBV/HDV combinations. To investigate the sensitivity of various combinations of HBV/HDV genotypes to BLV, clinical and laboratory strains were assessed. Methods: For the laboratory strains, the different envelopes from HBV genotypes A through H were combined with HDV genotypes 1–8 in cotransfection assays. Clinical plasma isolates were obtained from clinical studies and academic collaborations to maximise the diversity of HBV/HDV genotypes tested. Results: The mean BLV EC50 against HDV laboratory strains ranged from 0.44 to 0.64 nM. Regardless of HBV and HDV genotypes, the clinical isolates showed similar sensitivities to BLV with mean values that ranged from 0.2 to 0.73 nM. Conclusions: These data support the use of BLV in patients infected with any HBV/HDV genotypes. Impact and implications: This study describes the potent activity of BLV against multiple laboratory strains spanning all HBV/HDV A–H/1–8 genotype combinations and the most diverse collection of HDV clinical samples tested to date, including HBV/HDV genotype combinations less frequently observed in the clinic. Overall, all isolates and laboratory strains displayed similar in vitro nanomolar sensitivity to BLV. This broad-spectrum antiviral activity of BLV has direct implications on potential simplified treatment for any patient infected with HDV, regardless of genotype, and supports the new 2023 EASL Clinical Practice Guidelines on HDV that recommend antiviral treatment for all patients with CHD.

Published
2023
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4. Hepatitis D virus infection: Pathophysiology, epidemiology and treatment. Report from the first international delta cure meeting 2022Key points

Author

Pietro Lampertico, Elisabetta Degasperi, Lisa Sandmann, Heiner Wedemeyer, Cihan Yurdaydin, Dominique Roulot, Fabien Zoulim, Florin Alexandru Caruntu, Helenie Kefalakes, Julie Lucifora, Kosh Agarwal, Laurent Castera, Maria Buti, Mario Rizzetto, Markus Cornberg, Maura Dandri, Maurizia Brunetto, Nancy Reau, Robert Gish, Saeed Hamid, Soo Aleman, Stephan Urban, Tarik Asselah, Thomas Berg, and Victor de Lédinghen

Subjects
Chronic hepatitis Delta, HDV, HDV RNA, cirrhosis, Entry Inhibitor, Bulevirtide, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Summary: Chronic infection with hepatitis delta virus (HDV) affects between 12-20 million people worldwide and represents the most severe form of viral hepatitis, leading to accelerated liver disease progression, cirrhosis and its complications, such as end-stage-liver disease and hepatocellular carcinoma. From the discovery of HDV in 1977 by Prof. Mario Rizzetto, knowledge on the HDV life cycle and mechanisms of viral spread has expanded. However, little is still known about the natural history of the disease, host-viral interactions, and the role of the immune system in HDV persistence. Diagnosis of HDV is still challenging due to a lack of standardised assays, while accurate viral load quantification is needed to assess response and endpoints of antiviral treatment. Until recently, interferon has represented the only treatment option in patients with chronic hepatitis delta; however, it is associated with low efficacy and a high burden of side effects. The discovery of the entry inhibitor bulevirtide has represented a breakthrough in HDV treatment, by demonstrating high rates of viral suppression in phase II and III trials, results which have been confirmed in real-world settings and in patients with compensated advanced liver disease. In the meantime, other compounds (i.e. lonafarnib, new anti-hepatitis B virus drugs) are under development to provide alternative or combined strategies for HDV cure. The first international Delta Cure meeting was organised in Milan in October 2022 with the aim of sharing and disseminating the latest data; this review summarises key takeaway messages from state-of-the-art lectures and research data on HDV.

Published
2023
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5. Usefulness of the SAF score to characterize NAFLD/NASH in non-cirrhotic HCV patients

Author

Ahmed El Ray, Valerie Paradis, Ahmed Montasser, Maged Elghannam, Mohamed Shemis, Iris Nessim, Hoda Abu-Taleb, Tarik Asselah, Ashiq Mohamed, Nicolas Poté, Maha Akl, and Patrick Marcellin

Subjects
SAF, Steatosis, Activity, Fibrosis, NAFLD, NASH, Surgery, RD1-811, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Abstract Background The SAF score (steatosis, activity, and fibrosis) has been developed for the assessment of the histological severity of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). The aim of this study was to assess the usefulness of the SAF score in a homogenous cohort of Egyptian patients with chronic HCV infection (CHC) without any alcohol consumption and without cirrhosis. We performed a prospective cross-sectional study including 70 consecutive Egyptian patients with chronic HCV infection to assess the usefulness of the SAF score to characterize NAFLD/NASH in non-cirrhotic HCV patients. The inclusion criteria included positive serum anti-HCV IgG antibody and positive HCVRNA, absence of treatment, and absence of cirrhosis (fibrosis score < F4). Patients were divided into two groups: with metabolic syndrome (MS) and without metabolic syndrome (non-MS). All patients were exposed to thorough history taking, full clinical examination, and laboratory and ultrasound assessment. Histopathologic evaluation of the liver biopsy for the assessment of steatosis, activity, grade, and fibrosis stage was assessed by 2 pathologists with experience in liver diseases. Results We found that the degree of fibrosis increases with aging. Liver biopsies from CHC patients with metabolic syndrome (MS) exhibited a significantly higher stage of fibrosis than biopsies from those without MS; however, the grade of inflammation did not differ significantly between the two groups. No significant correlation was found between the SAF score and the body mass index (BMI) or serum HCV RNA. No significant relation between SAF score, fibrosis, and MS. No significant relation was found between the MS and the level of HCV viremia. Conclusion We concluded that steatosis was associated with the fibrosis stage, independently of MS. This suggests that in this population, steatosis might be more related to HCV infection than to NAFLD and that fibrosis progression might be related, at least in part, to the steatosis process, i.e., virus-associated fatty liver disease (VAFLD).

Published
2022
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6. Clinical outcomes after treatment with direct antiviral agents: beyond the virological response in patients with previous HCV-related decompensated cirrhosis

Author

Georges-Philippe Pageaux, Clovis Lusivika Nzinga, Nathalie Ganne, Didier Samuel, Céline Dorival, Fabien Zoulim, Carole Cagnot, Thomas Decaens, Dominique Thabut, Tarik Asselah, Philippe Mathurin, François Habersetzer, Jean-Pierre Bronowicki, Dominique Guyader, Isabelle Rosa, Vincent Leroy, Olivier Chazouilleres, Victor de Ledinghen, Marc Bourliere, Xavier Causse, Paul Cales, Sophie Metivier, Véronique Loustaud-Ratti, Ghassan Riachi, Laurent Alric, Moana Gelu-Simeon, Anne Minello, Jérôme Gournay, Claire Geist, Albert Tran, Armand Abergel, Isabelle Portal, Louis d’Alteroche, François Raffi, Hélène Fontaine, Fabrice Carrat, Stanislas Pol, and For the French ANRS CO22 Hepather Cohort

Subjects
Hepatitis C virus, Decompensated cirrhosis, Direst-acting antiviral agents, Survival, Hepatocellular carcinoma, Sustained virological response, Infectious and parasitic diseases, RC109-216
Abstract

Abstract Background In HCV-infected patients with advanced liver disease, the direct antiviral agents-associated clinical benefits remain debated. We compared the clinical outcome of patients with a previous history of decompensated cirrhosis following treatment or not with direct antiviral agents from the French ANRS CO22 HEPATHER cohort. Methods We identified HCV patients who had experienced an episode of decompensated cirrhosis. Study outcomes were all-cause mortality, liver-related or non-liver-related deaths, hepatocellular carcinoma, liver transplantation. Secondary study outcomes were sustained virological response and its clinical benefits. Results 559 patients met the identification criteria, of which 483 received direct antiviral agents and 76 remained untreated after inclusion in the cohort. The median follow-up time was 39.7 (IQR: 22.7–51) months. After adjustment for multivariate analysis, exposure to direct antiviral agents was associated with a decrease in all-cause mortality (HR 0.45, 95% CI 0.24–0.84, p = 0.01) and non-liver-related death (HR 0.26, 95% CI 0.08–0.82, p = 0.02), and was not associated with liver-related death, decrease in hepatocellular carcinoma and need for liver transplantation. The sustained virological response was 88%. According to adjusted multivariable analysis, sustained virological response achievement was associated with a decrease in all-cause mortality (HR 0.29, 95% CI 0.15–0.54, p

Published
2022
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7. Impact of cirrhosis aetiology on incidence and prognosis of hepatocellular carcinoma diagnosed during surveillance

Author

Nathalie Ganne-Carrié, Pierre Nahon, Cendrine Chaffaut, Gisèle N’Kontchou, Richard Layese, Etienne Audureau, Sylvie Chevret, Isabelle Archambeaud, Louis d’Alteroche, Frédéric Oberti, Dominique Roulot, Christophe Moreno, Alexandre Louvet, Thông Dao, Romain Moirand, Odile Goria, Eric Nguyen-Khac, Nicolas Carbonell, Jean-Charles Duclos-Vallée, Stanislas Pol, Victor de Ledinghen, Violaine Ozenne, Jean Henrion, Jean-Marie Péron, Albert Tran, Gabriel Perlemuter, Xavier Amiot, Jean-Pierre Zarski, Tarik Asselah, Dominique Guyader, Hélène Fontaine, Georges-Philippe Pageaux, Victor De Lédinghen, Denis Ouzan, Fabien Zoulim, Jean-Pierre Bronowicki, Thomas Decaens, Ghassan Riachi, Paul Calès, Laurent Alric, Marc Bourlière, Philippe Mathurin, Sebastien Dharancy, Jean-Frédéric Blanc, Armand Abergel, Olivier Chazouillères, Ariane Mallat, Jean-Didier Grangé, Pierre Attali, Claire Wartelle, Dominique Thabut, Christophe Pilette, Christine Silvain, Christos Christidis, Brigitte Bernard-Chabert, Sophie Hillaire, and Vincent Di Martino

Subjects
alcoholic liver disease, cirrhosis, primary liver cancer, competing risk analysis, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background & Aims: In this study we aimed to analyse the impact of the aetiology of cirrhosis on the incidence, characteristics and prognosis of hepatocellular carcinoma (HCC) diagnosed during a surveillance program. Methods: Individual data from a randomized trial and 2 prospective cohorts of patients with compensated histologically proven cirrhosis recruited between 2000 and 2016 were pooled. The influence of cirrhosis aetiology on survival after HCC detection was assessed using multivariable regression models. Results: Among 3,533 patients (1,926 virus [VIR], 1,167 alcohol [ALC], 440 combined [MIX]), 431 were diagnosed with HCC after a median follow-up of 57.1 months. The 5-year HCC incidence was lowest in ALC (VIR 12.6%, ALC 9.1%, MIX 14.3%, p = 0.04). At the time of diagnosis, tumour burden and Child-Pugh score were comparable across aetiology groups, but early BCLC stages (0/A) were significantly less frequent in ALC (VIR 80%, ALC 37%, MIX 72%) as a result of worse ECOG performance status. However, similar access to first-line curative HCC treatment was reported across aetiology groups (p = 0.68). Median survival after HCC diagnosis was significantly reduced in ALC (VIR 39, ALC 21, MIX 34 months, p = 0.02). However, when adjusting for tumour size, ECOG and Child-Pugh score, the aetiology of the underlying cirrhosis no longer had a significant impact. Conclusion: Compared to patients with virus-related cirrhosis, patients with alcohol-related compensated cirrhosis enrolled in a surveillance program have: i) the lowest 5-year HCC incidence; ii) worse overall prognosis, mostly driven by a poor general condition, despite similar access to first-line curative treatment. Lay summary: It has been suggested that early detection of hepatocellular carcinoma (HCC) may be futile in patients with alcohol-related cirrhosis. By comparing outcomes in more than 3,000 patients with compensated cirrhosis included in surveillance programs, this study suggests that HCC surveillance enables early diagnosis in most patients with alcohol-related cirrhosis despite a higher competing risk of death in these patients. We also report similar access to first-line curative HCC treatment in these patients compared to those with viral cirrhosis, despite higher rates of comorbidities and impaired liver function. Following HCC detection, the later parameters were major drivers of death irrespective of the cause of cirrhosis. Registration: CHC2000 (NCT00190385) and CIRRAL (NCT01213927) cohorts were registered at ClinicalTrials.gov and the full protocols are available at the following links (https://clinicaltrials.gov/ct2/show/NCT00190385) and https://clinicaltrials.gov/ct2/show/NCT01213927, respectively). The full CirVir protocol is available via the ANRS Web site (http://anrs.fr).

Published
2021
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8. Treatment efficacy of ledipasvir/sofosbuvir for 8 weeks in non-cirrhotic chronic hepatitis C genotype 4 patients

Author

Mohammed A Babatin, Abdullah S AlGhamdi, Abdullah M Assiri, Haziz AlBiladi, Hammad S AlOthmani, Mohammed H Mogharbel, Wedad Mahallawi, Tarik Asselah, and Faisal M Sanai

Subjects
Duration, genotype 4, hepatitis C, ledipasvir, sofosbuvir, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background/Aims: Ledipasvir/sofosbuvir (LDV/SOF) combination is administered for 12 to 24 weeks to treat hepatitis C virus (HCV); guidelines recommend 8 weeks treatment duration for HCV genotype (GT) 1 infection based on the patient's baseline characteristics. Data on treating HCV GT4 with LDV/SOF are limited. In this prospective cohort study, the efficacy and safety of 8 weeks treatment duration with LDV/SOF was evaluated in HCV GT4 patients in Saudi Arabia. Patients and Methods: Treatment-naïve, non-cirrhotic HCV GT4 patients received LDV/SOF for 8 weeks. HCV RNA levels and laboratory evaluations were recorded at baseline and at Weeks 4, 8, and 20. The primary endpoint was sustained virologic response 12 weeks after the end of the treatment (SVR12). Safety data were also recorded. Results: Forty-five patients with a mean age of 43.9 ± 17.2 years participated, of whom 57.8% were male. Mean log10HCV RNA was 6.26 ± 6.32 IU/mL and most (91.1%) had baseline HCV RNA levels

Published
2019
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9. Metabolic Disorders in Patients with Chronic Hepatitis B Virus Infection: Coffee as a Panacea? (ANRS CO22 Hepather Cohort)

Author

Tangui Barré, Hélène Fontaine, Stanislas Pol, Clémence Ramier, Vincent Di Beo, Camelia Protopopescu, Fabienne Marcellin, Morgane Bureau, Marc Bourlière, Céline Dorival, Ventzislava Petrov-Sanchez, Tarik Asselah, Elisabeth Delarocque-Astagneau, Dominique Larrey, Jean-Charles Duclos-Vallée, Fabrice Carrat, Patrizia Carrieri, and on behalf of the ANRS/AFEF Hepather Study Group

Subjects
coffee, tea, hepatitis B, metabolic syndrome, dyslipidemia, hypertension, Therapeutics. Pharmacology, RM1-950
Abstract

People living with chronic hepatitis B virus (HBV) infection are at high risk of liver disease progression, which is positively associated with metabolic disorders, but inversely associated with dyslipidemia. Diet, including dietary antioxidants, is a lever of metabolic disorder management. In particular, elevated coffee consumption is associated with different metabolic outcomes in the general population. We aimed to test whether such associations occur in HBV-infected people. Based on cross-sectional data from the ANRS CO22 Hepather cohort, we performed logistic regression models with (i) dyslipidemia, (ii) hypertension, and (iii) diabetes as outcomes, and with demographic, clinical, and socio-behavioral (including coffee consumption) data as explanatory variables. Among 4746 HBV-infected patients, drinking ≥3 cups of coffee per day was associated with a higher risk of dyslipidemia (adjusted odds ratio [95% confidence interval] 1.49 [1.10–2.00], p = 0.009) and a lower risk of hypertension (0.64 [0.50–0.82], p = 0.001). It was not associated with diabetes. Elevated coffee consumption was associated with a higher risk of dyslipidemia and a lower risk of hypertension in HBV-infected patients, two effects expected to be associated with favorable clinical outcomes. Further studies should test whether such metabolic benefits translate into reduced mortality risk in this population.

Published
2022
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10. Final analysis of the international observational S-Collate study of peginterferon alfa-2a in patients with chronic hepatitis B.

Author

Patrick Marcellin, Qing Xie, Seung Woon Paik, Robert Flisiak, Teerha Piratvisuth, Jörg Petersen, Tarik Asselah, Markus Cornberg, Denis Ouzan, Graham R Foster, Georgios Papatheodoridis, Diethelm Messinger, Loredana Regep, Georgios Bakalos, Ulrich Alshuth, Pietro Lampertico, and Heiner Wedemeyer

Subjects
Medicine, Science
Abstract

BACKGROUND AND AIMS:Sustained off-treatment immune control is achievable in a proportion of patients with chronic hepatitis B treated with peginterferon alfa-2a. We evaluated on-treatment predictors of hepatitis B surface antigen (HBsAg) clearance 3 years after peginterferon alfa-2a treatment and determined the incidence of hepatocellular carcinoma. METHODS:A prospective, international, multicenter, observational study in patients with chronic hepatitis B who have been prescribed peginterferon alfa-2a (40KD) in a real-world setting. The primary endpoint was HBsAg clearance after 3 years' follow-up. RESULTS:The modified intention-to-treat population comprised 844 hepatitis B e antigen (HBeAg)-positive patients (540 [64%] completed 3 years' follow-up), and 872 HBeAg-negative patients (614 [70%] completed 3 years' follow-up). At 3 years' follow-up, HBsAg clearance rates in HBeAg-positive and HBeAg-negative populations, respectively, were 2% (16/844) and 5% (41/872) in the modified intention-to-treat population and 5% [16/328] and 10% [41/394] in those with available data. In HBeAg-positive patients with data, Week 12 HBsAg levels 20,000 IU/mL were associated with HBsAg clearance rates at 3 years' follow-up of 11%, 1%, and 5%, respectively (Week 24 predictability was similar). In HBeAg-negative patients with available data, a ≥10% decline vs a

Published
2020
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12. Safety and efficacy of glecaprevir/pibrentasvir for the treatment of chronic hepatitis C in patients aged 65 years or older.

Author

Graham R Foster, Tarik Asselah, Sarah Kopecky-Bromberg, Yang Lei, Armen Asatryan, Roger Trinh, Neddie Zadeikis, and Federico J Mensa

Subjects
Medicine, Science
Abstract

Finding safe and effective treatments for chronic hepatitis C virus (HCV) infection in the elderly is of clinical interest given the comorbidities and associated polypharmacy in this population. However, the number of patients older than age 65 years enrolled into clinical trials of anti-HCV medications generally have been limited and thus reaching meaningful conclusions for this demographic has been difficult. Glecaprevir/pibrentasvir is a once-daily, all-oral, ribavirin-free, pangenotypic direct-acting antiviral (DAA) combination therapy that has demonstrated high sustained virologic response rates at post-treatment week 12 (SVR12) and a favorable safety profile in patients with chronic HCV infection. This analysis evaluated the safety and efficacy of glecaprevir/pibrentasvir in patients aged ≥65 years. Data were pooled for treatment-naïve and -experienced patients with chronic HCV genotype (GT) 1-6 infections who received glecaprevir/pibrentasvir for 8, 12, or 16 weeks in 9 Phase 2 and 3 trials. SVR12 and adverse events (AEs) were evaluated for patients aged ≥65 versus

Published
2019
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13. miRNAs as Potential Biomarkers for Viral Hepatitis B and C

Author

Dimitri Loureiro, Issam Tout, Stéphanie Narguet, Sabrina Menasria Benazzouz, Abdellah Mansouri, and Tarik Asselah

Subjects
liver, inflammation, chronic liver diseases, chronic hepatitis, fibrosis markers, pro-fibrogenic, Microbiology, QR1-502
Abstract

Around 257 million people are living with hepatitis B virus (HBV) chronic infection and 71 million with hepatitis C virus (HCV) chronic infection. Both HBV and HCV infections can lead to liver complications such as cirrhosis and hepatocellular carcinoma (HCC). To take care of these chronically infected patients, one strategy is to diagnose the early stage of fibrosis in order to treat them as soon as possible to decrease the risk of HCC development. microRNAs (or miRNAs) are small non-coding RNAs which regulate many cellular processes in metazoans. Their expressions were frequently modulated by up- or down-regulation during fibrosis progression. In the serum of patients with HBV chronic infection (CHB), miR-122 and miR-185 expressions are increased, while miR-29, -143, -21 and miR-223 expressions are decreased during fibrosis progression. In the serum of patients with HCV chronic infection (CHC), miR-143 and miR-223 expressions are increased, while miR-122 expression is decreased during fibrosis progression. This review aims to summarize current knowledge of principal miRNAs modulation involved in fibrosis progression during chronic hepatitis B/C infections. Furthermore, we also discuss the potential use of miRNAs as non-invasive biomarkers to diagnose fibrosis with the intention of prioritizing patients with advanced fibrosis for treatment and surveillance.

Published
2020
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14. Faldaprevir, pegylated interferon, and ribavirin for treatment-naïve HCV genotype-1: pooled analysis of two phase 3 trials

Author

Donald M. Jensen, Tarik Asselah, Douglas Dieterich, Graham R. Foster, Mark S. Sulkowski, Stefan Zeuzem, Parvez Mantry, Eric M. Yoshida, Christophe Moreno, Denis Ouzan, Mark Wright, Luis E. Morano, Robert Buynak, Marc Bourlière, Tarek Hassanein, Shuhei Nishiguchi, Jia-Horng Kao, Masao Omata, Seung W. Paik, David K. Wong, Edward Tam, Kelly Kaita, S. Victor Feinman, Jerry O. Stern, Joseph Scherer, Anne-Marie Quinson, Florian Voss, John-Paul Gallivan, Wulf O. Böcher, and Peter Ferenci

Subjects
Hepatitis C, Viral hepatitis, Direct-acting antiviral, SVR12, Specialties of internal medicine, RC581-951
Abstract

Introduction & aim. Faldaprevir is a potent once-daily (q.d.) hepatitis C virus (HCV) NS3/4A protease inhibitor. The STARTVerso1 and STARTVerso2 phase 3 studies evaluated faldaprevir plus peginterferon alfa-2a/ribavirin (PegIFN/RBV) in treatment-naïve patients with chronic HCV genotype-1 infection.Material and methods. Patients were randomized 1:2:2 to receive placebo, faldaprevir 120 mg q.d. (12 or 24 weeks) or faldaprevir 240 mg q.d. (12 weeks) all with PegIFN/RBV (24-48 weeks). Faldaprevir 120 mg for 12 weeks only (STARTVerso1 only) required early treatment success (ETS, HCV RNA < 25 IU/mL at week 4 and undetected at week 8). All faldaprevir-treated patients with ETS stopped PegIFN/RBV at week 24. Primary endpoint: sustained virologic response 12 weeks post-treatment (SVR12).Results. SVR12 rates were significantly higher for patients treated with faldaprevir 120 or 240 mg (72% and 73%, respectively) compared with placebo (50%); estimated differences (adjusted for trial, race, and genotype-1 subtype) faldaprevir 120 mg 24% (95% CI: 17-31%, P < 0.0001), faldaprevir 240 mg 23% (95% CI: 16-30%, P < 0.0001). Subgroup analyses consistently showed higher SVR12 rates for patients receiving faldaprevir compared with placebo. The incidence of adverse events (AEs) was similar in faldaprevir 120-mg and placebo groups and slightly higher in the faldaprevir 240-mg group. Serious AEs were reported in 6%, 7%, and 8% of patients in placebo, faldaprevir 120-mg, and faldaprevir 240-mg groups, respectively.Conclusion. Addition of faldaprevir to PegIFN/RBV increased SVR12 in patients with HCV genotype-1, and was well tolerated. Faldaprevir 120 mg is effective in the treatment of HCV genotype-1. ClinicalTrials.gov: NCT01343888 and NCT01297270.

Published
2016
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15. Efficacy of a 12-Week Simeprevir Plus Peginterferon/Ribavirin (PR) Regimen in Treatment-Naïve Patients with Hepatitis C Virus (HCV) Genotype 4 (GT4) Infection and Mild-To-Moderate Fibrosis Displaying Early On-Treatment Virologic Response.

Author

Tarik Asselah, Christophe Moreno, Christoph Sarrazin, Michael Gschwantler, Graham R Foster, Antonio Craxí, Peter Buggisch, Faisal Sanai, Ceyhun Bicer, Oliver Lenz, Gino Van Dooren, Catherine Nalpas, Isabelle Lonjon-Domanec, Michael Schlag, and Maria Buti

Subjects
Medicine, Science
Abstract

BACKGROUND:HCV GT4 accounts for up to 20% of HCV infections worldwide. Simeprevir, given for 12 weeks as part of a 24- or 48-week combination regimen with PR is approved for the treatment of chronic HCV GT4 infection. Primary study objectives were assessment of efficacy and safety of simeprevir plus PR in treatment-naïve patients with HCV GT4 treated for 12 weeks. Primary efficacy outcome was sustained virologic response 12 weeks post-treatment (SVR12). Additional objectives included investigation of potential associations of rapid virologic response and baseline factors with SVR12. METHODS:This multicentre, open-label, single-arm study (NCT01846832) evaluated efficacy and safety of simeprevir plus PR in 67 patients with HCV GT4 infection. Patients were treatment-naïve, aged 18-70 years with METAVIR F0-F2 fibrosis. Patients with early virologic response (HCV RNA

Published
2017
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16. An Open-Label Trial of 12-Week Simeprevir plus Peginterferon/Ribavirin (PR) in Treatment-Naïve Patients with Hepatitis C Virus (HCV) Genotype 1 (GT1).

Author

Tarik Asselah, Christophe Moreno, Christoph Sarrazin, Michael Gschwantler, Graham R Foster, Antonio Craxí, Peter Buggisch, Robert Ryan, Oliver Lenz, Jane Scott, Gino Van Dooren, Isabelle Lonjon-Domanec, Michael Schlag, and Maria Buti

Subjects
Medicine, Science
Abstract

Shortening duration of peginterferon-based HCV treatment reduces associated burden for patients. Primary objectives of this study were to assess the efficacy against the minimally acceptable response rate 12 weeks post-treatment (SVR12) and safety of simeprevir plus PR in treatment-naïve HCV GT1 patients treated for 12 weeks. Additional objectives included the investigation of potential associations of rapid viral response and baseline factors with SVR12.In this Phase III, open-label study in treatment-naïve HCV GT1 patients with F0-F2 fibrosis, patients with HCV-RNA 12-week regimen.Overall SVR12 rate (66%) was below the target of 80%, indicating that shortening of treatment with simeprevir plus PR to 12 weeks based on very early response is not effective. However, baseline factors associated with higher SVR12 rates were identified. Therefore, while Week 2 response alone is insufficient to predict efficacy, GT1 patients with favourable baseline factors may benefit from a shortened simeprevir plus PR regimen.ClinicalTrials.gov NCT01846832.

Published
2016
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17. A Predictive Model for Selecting Patients with HCV Genotype 3 Chronic Infection with a High Probability of Sustained Virological Response to Peginterferon Alfa-2a/Ribavirin.

Author

Tarik Asselah, Alex J Thompson, Robert Flisiak, Manuel Romero-Gomez, Diethelm Messinger, Georgios Bakalos, and Mitchell L Shiffman

Subjects
Medicine, Science
Abstract

BACKGROUND:Access to direct-acting antiviral agents (DAAs) is restricted in some settings; thus, the European Association for the Study of the Liver recommends dual peginterferon/ribavirin (PegIFN/RBV) therapy wherever DAAs are unavailable. HCV genotype (GT) 3 infection is now the most difficult genotype to eradicate and PegIFN/RBV remains an effective option. The goal of this study was to devise a simple predictive score to identify GT3 patients with a high probability of achieving a sustained virologic response (SVR) with PegIFN alfa-2a/RBV therapy. METHODS:Relationships between baseline characteristics and SVR were explored by multiple logistic regression models and used to develop a simple scoring system to predict SVR using data from 1239 treatment-naive GT3 patients who received PegIFN alfa-2a/RBV for 24 weeks in two large observational cohort studies. RESULTS:The score was validated using a database of 473 patients. Scores were assigned for six factors as follows: age (years) (≤40: 2 points; >40 but ≤55: 1); bodyweight (kg) (200: 2; ≥100 but

Published
2016
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18. P16 SOF/VEL/VOX for 8 or 12 weeks results in high SVR12 rates: an integrated analysis of the POLARIS-1, POLARIS-2, POLARIS-3 AND POLARIS-4 studies

Author

Stuart K. Roberts, Curtis L. Cooper, Eric Lawitz, K. Rajender Reddy, Alex J. Thompson, Stefan Zeuzem, Ira M. Jacobson, Peter Ruane, Robert H. Hyland, Luisa M. Stamm, Lingling Han, Diana M. Brainard, Norbert Bräu, Tarik Asselah, Bernard E. Willems, Steven Flamm, Marc Bourlière, Graham R. Foster, Edward J. Gane, Michael Manns, Stuart C. Gordon, and Kris Kowdley

Subjects
Microbiology, QR1-502, Public aspects of medicine, RA1-1270
Published
2017
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19. IFI35, mir-99a and HCV genotype to predict sustained virological response to pegylated-interferon plus ribavirin in chronic hepatitis C.

Author

Emilie Estrabaud, Kevin Appourchaux, Ivan Bièche, Fabrice Carrat, Martine Lapalus, Olivier Lada, Michelle Martinot-Peignoux, Nathalie Boyer, Patrick Marcellin, Michel Vidaud, and Tarik Asselah

Subjects
Medicine, Science
Abstract

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

Published
2015
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20. ITPA Genotypes Predict Anemia but Do Not Affect Virological Response with Interferon-Free Faldaprevir, Deleobuvir, and Ribavirin for HCV Infection.

Author

Tarik Asselah, Stefan Zeuzem, Vicente Soriano, Jean-Pierre Bronowicki, Ansgar W Lohse, Beat Müllhaupt, Marcus Schuchmann, Marc Bourlière, Maria Buti, Stuart K Roberts, Edward J Gane, Jerry O Stern, Florian Voss, Patrick Baum, John-Paul Gallivan, Wulf O Böcher, and Federico J Mensa

Subjects
Medicine, Science
Abstract

BACKGROUND & AIM:Whether inosine triphosphatase (ITPA) gene polymorphisms predict anemia during interferon-free therapy in chronic hepatitis C virus (HCV)-infected patients is unknown. We examined the relationship between two ITPA polymorphisms, anemia, and sustained virological response 12 weeks post-treatment (SVR12) in patients receiving the NS3/4A protease inhibitor faldaprevir, the non-nucleoside polymerase inhibitor deleobuvir, and ribavirin. METHODS:HCV genotype 1-infected, treatment-naïve patients (N = 362) were randomized and treated in one of five treatment arms with faldaprevir and deleobuvir with or without ribavirin. Two ITPA polymorphisms (rs1127354 and rs6051702) were genotyped and defined as ITPA-deficient (rs1127354 AA or AC; rs6051702 CC or CA) or ITPA-non-deficient (rs1127354 CC; rs6051702 AA) according to their association with ITPA deficiency. Baseline and on-treatment variables associated with anemia and SVR12 were identified using logistic regression. RESULTS:In the pooled ribavirin-containing arms, 10.1% (32/316) of patients experienced on-treatment hemoglobin

Published
2015
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21. Randomised phase 2 study (JADE) of the HBV capsid assembly modulator JNJ-56136379 with or without a nucleos(t)ide analogue in patients with chronic hepatitis B infection

Author

Harry L A Janssen, Jinlin Hou, Tarik Asselah, Henry L Y Chan, Fabien Zoulim, Yasuhito Tanaka, Ewa Janczewska, Ronald G Nahass, Stefan Bourgeois, Maria Buti, Pietro Lampertico, Oliver Lenz, Thierry Verbinnen, Joris Vandenbossche, Willem Talloen, Ronald Kalmeijer, Maria Beumont, Michael Biermer, Umesh Shukla, Gastroenterology & Hepatology, Institut Català de la Salut, [Janssen HLA] Toronto General Hospital, Toronto, Ontario, Canada. Erasmus Medical Center, Rotterdam, Zuid-Holland, The Netherlands. [Hou J] Nanfang Hospital, Southern Medical University, Guangzhou, China. [Asselah T] Université de Paris Cité, INSERM UMR1149, Hôpital Beaujon AP-HP, Clichy, France. [Chan HLY] The Chinese University of Hong Kong, Hong Kong SAR, China. [Zoulim F] Hospices Civils de Lyon and Lyon University & INSERM U1052-Cancer Research Institute of Lyon, Lyon, France. [Tanaka Y] Department of Gastroenterology and Hepatology, Kumamoto University, Kumamoto, Japan. [Buti M] Vall d’Hebron Hospital Universitari, Barcelona, Spain. CIBERHED del Instituto Carlos III, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
SDG 3 - Good Health and Well-being, Otros calificadores::/uso terapéutico [Otros calificadores], acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antiinfecciosos::antivíricos [COMPUESTOS QUÍMICOS Y DROGAS], Gastroenterology, Medicaments antivírics - Ús terapèutic, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Other subheadings::/therapeutic use [Other subheadings], Other subheadings::Other subheadings::/drug therapy [Other subheadings], Hepatitis B - Tractament, virosis::infecciones por virus ADN::infecciones por Hepadnaviridae::hepatitis B::hepatitis B crónica [ENFERMEDADES], Virus Diseases::DNA Virus Infections::Hepadnaviridae Infections::Hepatitis B::Hepatitis B, Chronic [DISEASES], Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Infective Agents::Antiviral Agents [CHEMICALS AND DRUGS]
Abstract

ObjectiveWe present the final analysis results of the phase 2 JADE study (ClinicalTrials.gov Identifier:NCT03361956).Design232 patients with chronic hepatitis B (CHB) not currently treated at study start (NCT) at study start or virologically suppressed were randomised to receive 75 mg (part 1) or 250 mg (part 2) JNJ-56136379, a hepatitis B virus (HBV)–capsid assembly modulator, one time per day or placebo with nucleos(t)ide analogue (NA) (tenofovir disoproxil fumarate/entecavir) or JNJ-56136379 alone (NCT-only) for ≥24 and ≤48 weeks.ResultsIn patients who are NCT hepatitis B e-antigen (HBeAg) positive, JNJ-56136379 75 mg+NA and 250 mg+NA showed limited mean (SE) hepatitis B surface antigen (HBsAg) declines (0.14 (0.10) and 0.41 (0.15), respectively) from baseline at Week 24 (primary endpoint; placebo+NA: 0.25 (0.11) log10international unit (IU)/mL).In patients who are NCT HBeAg positive, mean (SE) HBV DNA declines at Week 24 were 5.53 (0.23) and 5.88 (0.34) for JNJ-56136379 75 mg+NA and 250 mg+NA, respectively, versus 5.21 (0.42) log10IU/mL for placebo+NA. In NCT patients, mean (SE) HBV RNA declines were 2.96 (0.23) and 3.15 (0.33) versus 1.33 (0.32) log10copies/mL, respectively.Patients with HBsAg declines had HBeAg and hepatitis B core-related antigen (HBcrAg) declines and some early on-treatment isolated alanine aminotransferase flares. Viral breakthrough occurred with JNJ-56136379 monotherapy with the emerging resistant-variant T33N, but not with JNJ-56136379+NA. JNJ-56136379 treatment beyond Week 24 had a generally small additional effect on viral markers.No study treatment-related serious adverse events or clinically significant changes in laboratory parameters occurred.ConclusionsIn patients with non-cirrhotic CHB, JNJ-56136379+NA showed pronounced reductions in HBV DNA and HBV RNA, limited HBsAg or HBeAg declines in patients who are NCT HBeAg positive, and was well tolerated, but no clear benefit with regards to efficacy of JNJ-56136379 over NA was observed.

Published
2023

23. Non-invasive diagnosis and follow-up of chronic infection with hepatitis B virus

Author

Vincent Leroy, Stéphane Chevaliez, Marie Decraecker, Dominique Roulot, Jean Nana, Tarik Asselah, Xavier Causse, David Durantel, Vincent Thibaut, Nathalie Ganne-Carrié, Christophe Bureau, Victor de Lédinghen, Marc Bourlière, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Physiopathologie du cancer du foie, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Grenoble Alpes (UGA), CHU Grenoble, Hôpital Beaujon [AP-HP], Centre Hospitalier Régional d'Orléans (CHRO), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pontchaillou [Rennes], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Saint-Joseph [Marseille], Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), and Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
MESH: Humans, Hepatology, MESH: Hepatitis B, Chronic, [SDV]Life Sciences [q-bio], Gastroenterology, MESH: Follow-Up Studies, ab, MESH: DNA, Viral, MESH: Hepatitis B Surface Antigens, MESH: Hepatitis B virus, MESH: RNA, MESH: Liver Neoplasms, MESH: Persistent Infection, MESH: Liver Cirrhosis, MESH: Carcinoma, Hepatocellular, MESH: Hepatitis B e Antigens
Abstract

Diagnosis of chronic hepatitis B virus (HBV) infection, initial staging of infection and monitoring of treated and untreated patients are mainly based on clinical, biological and imaging criteria allowing a complete non-invasive management for the majority of patients. Along to the conventional virological tools, rapid diagnostic tests and blotting paper tests for HBV DNA are validated alternatives. After diagnosis, the initial work-up should include HIV, HCV and HDV serologies, HBeAg status, and HBsAg and HBV DNA quantification. Assessment of severity (inflammation and fibrosis) is based on ALT serum levels and non-invasive evaluation of liver fibrosis by elastography or blood tests, which must be interpreted cautiously using specific cutoffs and taking into account ALT levels. Taken together, these parameters allow disease classification and treatment decision. Decision of hepatocellular carcinoma screening by ultra-sound every six months may be difficult in non-cirrhotic patients and the use of risk-scores such as PAGE-B is encouraged. Chronic HBV infection often has a dynamic and often unpredictable profile and regular monitoring is mandatory. In untreated patients, regular (3-12 months) follow-up should include ALT and HBV DNA serum levels. Periodical HBsAg quantification and non-invasive evaluation of liver fibrosis may refine disease outcome and prognosis. In treated patients, checking efficacy is mainly based on HBV DNA negativity. In patients with advanced fibrosis, evolution of liver stiffness can be useful for portal hypertension evaluation, but its improvement should not be considered to stop hepatocellular carcinoma screening. Finally, new parameters (HBV RNA, HBcrAg) are promising but their use is still restricted for research.

Published
2022

24. Metabolic Disorders in Patients with Chronic Hepatitis B Virus Infection: Coffee as a Panacea? (ANRS CO22 Hepather Cohort)

Author

Group, Tangui Barré, Hélène Fontaine, Stanislas Pol, Clémence Ramier, Vincent Di Beo, Camelia Protopopescu, Fabienne Marcellin, Morgane Bureau, Marc Bourlière, Céline Dorival, Ventzislava Petrov-Sanchez, Tarik Asselah, Elisabeth Delarocque-Astagneau, Dominique Larrey, Jean-Charles Duclos-Vallée, Fabrice Carrat, Patrizia Carrieri, and on behalf of the ANRS/AFEF Hepather Study Group on behalf of the ANRS/AFEF Hepather Study

Subjects
coffee, tea, hepatitis B, metabolic syndrome, dyslipidemia, hypertension, polyphenol
Abstract

People living with chronic hepatitis B virus (HBV) infection are at high risk of liver disease progression, which is positively associated with metabolic disorders, but inversely associated with dyslipidemia. Diet, including dietary antioxidants, is a lever of metabolic disorder management. In particular, elevated coffee consumption is associated with different metabolic outcomes in the general population. We aimed to test whether such associations occur in HBV-infected people. Based on cross-sectional data from the ANRS CO22 Hepather cohort, we performed logistic regression models with (i) dyslipidemia, (ii) hypertension, and (iii) diabetes as outcomes, and with demographic, clinical, and socio-behavioral (including coffee consumption) data as explanatory variables. Among 4746 HBV-infected patients, drinking ≥3 cups of coffee per day was associated with a higher risk of dyslipidemia (adjusted odds ratio [95% confidence interval] 1.49 [1.10–2.00], p = 0.009) and a lower risk of hypertension (0.64 [0.50–0.82], p = 0.001). It was not associated with diabetes. Elevated coffee consumption was associated with a higher risk of dyslipidemia and a lower risk of hypertension in HBV-infected patients, two effects expected to be associated with favorable clinical outcomes. Further studies should test whether such metabolic benefits translate into reduced mortality risk in this population.

Published
2022
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25. Treatment efficacy of ledipasvir/sofosbuvir for 8 weeks in non-cirrhotic chronic hepatitis C genotype 4 patients

Author

Abdullah S. Alghamdi, Hammad S. Alothmani, Faisal M. Sanai, Mohammed H Mogharbel, Mohammed A. Babatin, Haziz Albiladi, Tarik Asselah, Wedad Mahallawi, and Abdullah M. Assiri

Subjects
Male, ledipasvir, Sofosbuvir, Sustained Virologic Response, Hepacivirus, Comorbidity, medicine.disease_cause, Gastroenterology, Cohort Studies, chemistry.chemical_compound, 0302 clinical medicine, Clinical endpoint, Prospective Studies, Prospective cohort study, biology, Hepatitis C, Middle Aged, Treatment Outcome, 030220 oncology & carcinogenesis, 030211 gastroenterology & hepatology, Original Article, Drug Therapy, Combination, Female, Uridine Monophosphate, Cohort study, medicine.drug, Ledipasvir, Adult, medicine.medical_specialty, Genotype, Hepatitis C virus, Saudi Arabia, sofosbuvir, Antiviral Agents, 03 medical and health sciences, Internal medicine, medicine, Humans, genotype 4, lcsh:RC799-869, Fluorenes, business.industry, Hepatitis C, Chronic, biology.organism_classification, medicine.disease, Duration, chemistry, lcsh:Diseases of the digestive system. Gastroenterology, Benzimidazoles, hepatitis C, business
Abstract

Background/Aims: Ledipasvir/sofosbuvir (LDV/SOF) combination is administered for 12 to 24 weeks to treat hepatitis C virus (HCV); guidelines recommend 8 weeks treatment duration for HCV genotype (GT) 1 infection based on the patient's baseline characteristics. Data on treating HCV GT4 with LDV/SOF are limited. In this prospective cohort study, the efficacy and safety of 8 weeks treatment duration with LDV/SOF was evaluated in HCV GT4 patients in Saudi Arabia. Patients and Methods: Treatment-naïve, non-cirrhotic HCV GT4 patients received LDV/SOF for 8 weeks. HCV RNA levels and laboratory evaluations were recorded at baseline and at Weeks 4, 8, and 20. The primary endpoint was sustained virologic response 12 weeks after the end of the treatment (SVR12). Safety data were also recorded. Results: Forty-five patients with a mean age of 43.9 ± 17.2 years participated, of whom 57.8% were male. Mean log10 HCV RNA was 6.26 ± 6.32 IU/mL and most (91.1%) had baseline HCV RNA levels

Published
2019

26. Predictive Factors for Hepatocellular Carcinoma in Chronic Hepatitis B Using Structural Equation Modeling: A Prospective Cohort Study

Author

Jean-Pierre Bronowicki, Clovis Lusivika-Nzinga, Jean-Charles Duclos-Vallée, Ghassan Riachi, Anne Minello, Thomas Decaens, Louis d’Alteroche, Fabrice Carrat, Isabelle Portal, François Raffi, Fabien Zoulim, Sophie Metivier, Véronique Loustaud-Ratti, François Habersetzer, Jérôme Gournay, Olivier Chazouillères, Paul Calès, Victor de Ledinghen, Xavier Causse, Stanislas Pol, Céline Dorival, Isabelle Rosa, Dominique Larrey, Tarik Asselah, Marc Bourlière, Claire Geist, Nathanael Lapidus, Laurent Lam, Moana Gelu-Simeon, Laurent Alric, Vincent Leroy, Hélène Fontaine, Armand Abergel, Nathalie Ganne, Dominique Thabut, Philippe Mathurin, Albert Tran, Dominique Guyader, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Saint-Joseph [Marseille], Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pathologies biliaires, fibrose et cancer du foie [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Interactions Virus-Hôte et Maladies Hépatiques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Virologie, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre Hépato-Biliaire [Hôpital Paul Brousse] (CHB), Hôpital Paul Brousse-Assistance Publique - Hôpitaux de Paris, CRHU Nancy, Physiopathologie des Maladies Inflammatoires de l'Intestin, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHI Créteil, Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Centre Hospitalier Régional d'Orléans (CHRO), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service d'hépatologie [CHU Saint-Antoine], CHU Pointe-à-Pitre/Abymes [Guadeloupe], Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation (IPPRITT), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), CHU Toulouse [Toulouse], Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC), CHU Rouen, Normandie Université (NU), Institut des Maladies de l'Appareil Digestif, Université de Nantes (UN), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Hospitalier Universitaire de Nice (CHU Nice), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), Institut Pascal (IP), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA)-Institut national polytechnique Clermont Auvergne (INP Clermont Auvergne), Université Clermont Auvergne (UCA)-Université Clermont Auvergne (UCA), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hôpital de la Timone [CHU - APHM] (TIMONE), Immunité Innée - Innate Immunity, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], The ANRS CO22 HEPATHER cohort is sponsored and funded by INSERM‐ANRS and conducted in collaboration with Association Française pour l'étude du Foie (AFEF). The cohort received supports from ANR (Agence Nationale de la Recherche), DGS (Direction Générale de la Santé), MSD, Janssen, Gilead, Abbvie, BMS, and Roche., Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Pathologies biliaires, fibrose et cancer du foie [CRSA], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service d'Hépato-gastro-entérologie [CHU Saint-Antoine], Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Jonchère, Laurent

Subjects
Male, Liver Cancer, medicine.medical_specialty, Hepatocarcinogenesis, Hepatitis B virus, Carcinoma, Hepatocellular, Epidemiology, medicine.medical_treatment, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, Liver transplantation, Sciences du Vivant [q-bio]/Cancer, medicine.disease_cause, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Hepatitis B, Chronic, [SDV.CAN] Life Sciences [q-bio]/Cancer, Risk Factors, Internal medicine, medicine, Humans, Prospective Studies, Prospective cohort study, Aged, Hepatology, business.industry, Liver Neoplasms, Carcinoma, Hepatocellular, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, digestive system diseases, 3. Good health, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Cohort, 030211 gastroenterology & hepatology, Metabolic syndrome, business, Liver cancer
Abstract

International audience; BACKGROUND and AIMS: The factors predicting hepatocellular carcinoma (HCC) occurrence in chronic hepatitis B need to be precisely known to improve its detection. We identified pathways and individual predictive factors associated with HCC in the ANRS CO22 HEPATHER cohort. METHODS: The study analyzed HBV-infected patients recruited at 32 French expert hepatology centers from August 6, 2012, to December 31, 2015. We excluded patients with chronic HCV, HDV and a history of HCC, decompensated cirrhosis or liver transplantation. Structural equation models were developed to characterize the causal pathways leading to HCC occurrence. The association between clinical characteristics (age, gender, body-mass index, liver fibrosis, alcohol consumption, smoking status, diabetes, hypertension, dyslipidemia, alpha-fetoprotein, HBV DNA levels, antiviral therapy) and incident HCC was quantified. RESULTS: Among the 4,489 patients included, 33 patients reported incident HCC. The median follow-up was 45.2 months. Age (β = 0.18 by decade, 95% CI 0.14-0.23), male gender (β = 0.23, 95% CI 0.18-0.29), metabolic syndrome (β = 0.28, 95% CI 0.22-0.33), alcohol consumption (β = 0.09, 95% CI 0.05-0.14) and HBV DNA (β = 0.25, 95% CI 0.17-0.34) had a significant and direct effect on the occurrence of advanced liver fibrosis. Liver fibrosis (β = 0.71, 95% CI 0.55-0.87) predicted, in turn, the occurrence of HCC. CONCLUSIONS: Liver fibrosis mediates the effects of age, gender, alcohol, metabolic syndrome and HBV DNA on the occurrence of HCC. Elderly men with chronic hepatitis B, risky alcohol use, advanced liver fibrosis, metabolic syndrome and high HBV DNA levels should be monitored closely to detect the development of HCC.

Published
2021

27. Perspectives on stopping nucleos(t)ide analogues therapy in patients with chronic hepatitis B

Author

Tarik Asselah, Issam Tout, Thomas Berg, Pietro Lampertico, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Milan, Leipzig University, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Università degli Studi di Milano = University of Milan (UNIMI), and CCSD, Accord Elsevier

Subjects
0301 basic medicine, Oncology, Hepatitis B virus, medicine.medical_specialty, HBsAg, Sustained Virologic Response, [SDV]Life Sciences [q-bio], 030106 microbiology, Immune control, Hbsag seroclearance, Antiviral Agents, 03 medical and health sciences, Hepatitis B, Chronic, Immune system, Chronic hepatitis, Virology, Internal medicine, Humans, Medicine, In patient, Relapse, HBV infection, NA discontinuation, Pharmacology, business.industry, Disease progression, Nucleosides, medicine.disease, digestive system diseases, 3. Good health, [SDV] Life Sciences [q-bio], Treatment Outcome, 030104 developmental biology, Withholding Treatment, Seroconversion, Hepatocellular carcinoma, Quantitative hbsag, business, Biomarkers, Quantitative HBsAg
Abstract

International audience; Long-term treatment with nucleos(t)ide analogs (NAs) is the current first line therapy for patients with chronic hepatitis B (CHB), recommended by most of the current guidelines. NAs prevent disease progression, liver failure, decrease the risk of hepatocellular carcinoma (HCC), and have favorable safety profiles. However, low rates of on-therapy functional cure (hepatitis B surface antigen [HBsAg] loss), which is regarded as the optimal end point, prevent many patients from stopping NA therapy with the need for a lifelong treatment. The higher likelihood of HBsAg loss associated with stopping as compared to continuing NAs has got a lot of attention recently. Recommendations regarding endpoints allowing for safely stopping NA therapy differ between international guidelines. Whereas in HBeAg-positive patients, HBeAg seroconversion with at least one year of consolidation therapy is an acceptable endpoint of treatment, the recommendations for HBeAg-negative ones differ. Some guidelines propose ≥3 years of HBV DNA undetectability to stop NA while others regard HBsAg loss as the only acceptable endpoint. Stopping NA can lead to substantial rates of virologic relapses and consequent ALT flares in some cases. Moreover, no reliable predictor(s) of post-NA relapses have been identified so far. Quantitative HBsAg is becoming an increasingly promising marker to predict safe NA cessation. On the other hand, investigating the role of the immune system in mediating sustained virologic responses after NA withdrawal is needed to suggest immunological biomarkers to safely stop NA. In this article, we will review relevant literature regarding NA stopping strategy and discuss promising viral and immunological biomarkers to predict antiviral responses and thus to help identify patients who are more likely to achieve HBsAg seroclearance.

Published
2021

28. COVID-19: Discovery, diagnostics and drug development

Author

Tarik Asselah, Eric Pasmant, Raymond F. Schinazi, George Lau, and David Durantel

Subjects
0301 basic medicine, viruses, CoVs, coronavirus, coronavirus, remdesivir, Review, medicine.disease_cause, 0302 clinical medicine, Risk Factors, Case fatality rate, Pandemic, Drug Discovery, Medicine, Coronaviridae, IL, Interleukin, SOC, standard of care, Coronavirus, Respiratory Distress Syndrome, biology, drug repurposing, pathogenesis, CT, computed tomography, Drug repositioning, Drug development, 030211 gastroenterology & hepatology, COVID-19, coronavirus disease 19, TMPRSS2, Transmembrane serine protease 2, R0, the reproduction number, aa, amino acid, Genome, Viral, IFN-α, interferon alpha, Antiviral Agents, Virus, WHO, World Health Organization, ER, endoplasmic reticulum, 03 medical and health sciences, Drug Development, ARDS, Acute respiratory distress syndrome, Humans, SARS, severe acute respiratory syndrome, Pandemics, Hepatology, business.industry, SARS-CoV-2, Drug Repositioning, COVID-19, biology.organism_classification, medicine.disease, Virology, ACE-2, Angiotensin-Converting Enzyme 2, ELISA, Enzyme-linked immunosorbent assays, FDA, Food and Drug Administration, Immunity, Innate, COVID-19 Drug Treatment, 030104 developmental biology, EMA, European Medicines Agency, business, Cytokine storm, HCQ, Hydroxychloroquine (HCQ)
Abstract

An epidemic of acute respiratory syndrome (Covid-19) started in humans in Wuhan in 2019, and became a pandemic. Groups from China Identified and sequenced the virus responsible for COVID-19, named SARS-CoV-2, and determined that it was a novel coronavirus (CoV) that shared high sequence identity with bat- and pangolin-derived SARS-like CoVs, suggesting a zoonotic origin. SARS-CoV-2 is a member of Coronaviridae, a family of enveloped, positive-sense, single-stranded RNA viruses that infect a broad range of vertebrates. The rapid release of the sequence of the virus has allowed the development of diagnostic tools (e.g., RT-PCR). Additionally, serological tests can allow identification of persons who have been infected. In humans, CoVs tend to cause mild to moderate upper respiratory tract infections. The fatality rate is around 1-3% for infected persons. An acute respiratory distress syndrome (ARDS) likely due to an uncontrolled immune activation (“cytokine storm”) occurs in patients with severe disease and poor prognosis. Risk factors for mortality include: advanced age, obesity, diabetes, hypertension and other comorbidities. Drug repurposing has been used to rapidly identify potential treatment for COVID-19, which could move quickly to phase-3. Better knowledge of the virus, its enzymes, will be mandatory to develop more potent and specific direct-acting antiviral agents (DAA). In the long term, a vaccine to prevent infection would be crucial; however even if successful it might not be available before 2021-22. To date, with the exception of intravenous Remdesivir and dexamethasone, which have modest effects in moderate to severe COVID-19, no strong clinical evidence supports the efficacy and safety of any other drugs against SARS-CoV-2. The aim of this review is to provide insights on the discovery of SARS-CoV-2, its virology, the diagnostic tools, and the ongoing drug discovery effort.

Published
2021
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29. The case for simplifying and using absolute targets for viral hepatitis elimination goals

Author

Tsendsuren S. Oyunsuren, Chari Cohen, Waseem Hamoudi, Yao‐Chun Hsu, Harry L.A. Janssen, Hisham El Khayat, Manal H El-Sayed, Wan-Long Chuang, Young-Suk Lim, Mohamed Hassany, Fernando Passos Cupertino de Barros, Faisal Abaalkhail, Stefan Zeuzem, Samual S Lee, Miriam T. Levy, Imam Waked, Vassiliki Papaevangelou, James Fung, Erika Castro Batänjer, Kathryn Razavi-Shearer, Boatemaa Ntiri‐ Reid, Rosmawati Mohamed, Pagbajabyn Nymadawa, Robert Flisiak, Alnoor Ramji, Carole Seguin-Devaux, Sherif Mogawer, Béla Hunyady, Huma Qureshi, Mojca Matičič, Martin Lagging, Mark W. Sonderup, Xiaoguang Dou, Anne Oevrehus, William Sievert, Ezequiel Ridruejo, Ann-Sofi Duberg, Ahad Eshraghian, R. P. Shanmugam, Arif Nawaz, Qing Xie, Rick Dunn, Sayed Himatt, Daniel Shouval, Mendez Sanchez Nahum, Sabahattin Kaymakoglu, Vincent Wai-Sun Wong, Soek-Siam Tan, Willis Maddrey, Papu Prasad, Amjad Salamat, Stephanie Popping, Alice Lee, Maurizia Rossana Brunetto, Khalid Alswat, Peyton Thompson, Dong Joon Kim, Henry Chang, Amir Ali Sohrabpour, Ellen Dugan, Peer Brehm Christensen, David A. M. C. van de Vijver, Joaquín Cabezas, Su Wang, Ala I. Sharara, Peter Jarcuska, Karine Lacombe, Danjuma Adda, Sammy Saab, Chien-Jen Chen, Hwai I. Yang, Sanaa Said, Raymond F. Schinazi, Shyamasundaran Kottilil, Graham R. Foster, Qing Ning, Mehlika Toy, Ira M. Jacobson, Ayat R. Abdallah, Laura Cisneros, Dhondup Tashi, Naveed Z. Janjua, Moutaz Derbala, Marcelo Kugelmas, Steven L. Flamm, Angelos Hatzakis, Yusuf Yilmaz, Mark S. Sulkowski, Eugene R. Schiff, Kakharman Yesmembetov, John F. Dillon, Rittoo Prithiviputh, Carlos Eduardo Brandão-Mello, Rajender Reddy, Françoise Roudot-Thoraval, Lewis R. Roberts, Javier Crespo, Massimo Colombo, Nancy Steinfurth, I. M. Hoepelman, Kosh Agarwal, Faisal M. Sanai, Waleed Al-Hamoudi, Shuang Liu, Beat Muellhaupt, Sonjelle Shilton, Curtis Cooper, Calvin Q. Pan, Aijaz Ahmed, Wai-cheung C Lao, Alejandro Soza, Patricia Vélez‐Möller, Ibrahim Altraif, Tarik Asselah, Junko Tanaka, Badr Aljarallah, Adriana Vince, Faryal Khamis, Juan Francisco Sánchez-Ávila, Rafael Esteban Mur, Kimberly A. Brown, Saad Al-Kaabi, Ming-Lung Yu, Jonas Valantinas, Marieta Simonova, Javier García-Samaniego, Do Young Kim, Ieva Tolmane, Valentina Liakina, Antonio Craxì, Devin Razavi-Shearer, Waldemar Halota, Stuart K. Roberts, Donna Cryer, Kenneth Kabagambe, William Remak, Jeffrey V. Lazarus, Brian Conway, Sameera Ezzat, C Wendy Spearman, Karolin Falconer, Maria C Mendes Correa, Poonam Mathur, Ferruccio Bonino, Jose Luis Calleja, Said A. Al-Busafi, E. A. Croes, Tim Block, Shahin Merat, Francesco Negro, Reza Malekzadeh, Fernando L. Gonçales, Amany Zekry, Wahid Doss, Michael Ninburg, Philip Bruggmann, Man-Fung Yuen, George V. Papatheodoridis, Aasim Yusuf, David Kershenobich, Bruce R. Bacon, Abdul Rahman Bizri, Gamal Esmat, Sarah Blach, Hamad Al-Romaihi, Tatsuya Kanto, Ibrahim Mostafa, Homie Razavi, Alessio Aghemo, Mauricio Orrego, Jia-Horng Kao, Daniel Lavanchy, Zobair M. Younossi, Henry Lik-Yuen Chan, Anna Kramvis, David H. Muljono, Clemens Richter, Hla-Hla Thein, Fernando Bessone, Paulo Roberto Abrão Ferreira, Geoffrey Dusheiko, Susan Hay, Geert Robaeys, Eduardo Fassio, Loreta A. Kondili, Jorge Mera, Khalid Al-Naamani, Alaa Osman, Saleh A. Alqahtani, Joseph Doyle, Necati Örmeci, Yee Tak Hui, Heiner Wedemeyer, Laith Jamal Abu Raddad, Masayuki Kurosaki, Rui Tato Marinho, Robert G. Gish, Zaigham Abbas, Seiji Yamada, Giada Sebastiani, Cihan Yurdaydin, Maria Buti, Paulo Ferrinho, Razavi H., Blach S., Razavi-Shearer D., Abaalkhail F., Abbas Z., Abdallah A., Abrao Ferreira P., Abu Raddad L.J., Adda D., Agarwal K., Aghemo A., Ahmed A., Al-Busafi S.A., Al-hamoudi W., Al-Kaabi S., Al-Romaihi H., Aljarallah B., AlNaamani K., Alqahtani S., Alswat K., Altraif I., Asselah T., Bacon B., Bessone F., Bizri A.R., Block T., Bonino F., Brandao-Mello C.E., Brown K., Bruggmann P., Brunetto M.R., Buti M., Cabezas J., Calleja J.L., Castro Batanjer E., Chan H.L.-Y., Chang H., Chen C.-J., Christensen P.B., Chuang W.-L., Cisneros L., Cohen C., Colombo M., Conway B., Cooper C., Craxi A., Crespo J., Croes E., Cryer D., Cupertino de Barros F.P., Derbala M., Dillon J., Doss W., Dou X., Doyle J., Duberg A.-S., Dugan E., Dunn R., Dusheiko G., El Khayat H., El-Sayed M.H., Eshraghian A., Esmat G., Esteban Mur R., Ezzat S., Falconer K., Fassio E., Ferrinho P., Flamm S., Flisiak R., Foster G., Fung J., Garcia-Samaniego J., Gish R.G., Goncales F., Halota W., Hamoudi W., Hassany M., Hatzakis A., Hay S., Himatt S., Hoepelman I.M., Hsu Y.-C., Hui Y.T., Hunyady B., Jacobson I., Janjua N., Janssen H., Jarcuska P., Kabagambe K., Kanto T., Kao J.-H., Kaymakoglu S., Kershenobich D., Khamis F., Kim D.J., Kim D.Y., Kondili L.A., Kottilil S., Kramvis A., Kugelmas M., Kurosaki M., Lacombe K., Lagging M., Lao W.-C., Lavanchy D., Lazarus J.V., Lee A., Lee S.S., Levy M., Liakina V., Lim Y.-S., Liu S., Maddrey W., Malekzadeh R., Marinho R.T., Mathur P., Maticic M., Mendes Correa M.C., Mera J., Merat S., Mogawer S., Mohamed R., Muellhaupt B., Muljono D., Mostafa I., Nahum M.S., Nawaz A., Negro F., Ninburg M., Ning Q., Ntiri- Reid B., Nymadawa P., Oevrehus A., Ormeci N., Orrego M., Osman A., Oyunsuren T., Pan C., Papaevangelou V., Papatheodoridis G., Popping S., Prasad P., Prithiviputh R., Qureshi H., Ramji A., Razavi-Shearer K., Reddy R., Remak W., Richter C., Ridruejo E., Robaeys G., Roberts S., Roberts L., Roudot-Thoraval F., Saab S., Said S., Salamat A., Sanai F., Sanchez-Avila J.F., Schiff E., Schinazi R., Sebastiani G., Seguin-Devaux C., Shanmugam R.P., Sharara A., Shilton S., Shouval D., Sievert W., Simonova M., Sohrabpour A.A., Sonderup M., Soza A., Wendy Spearman C., Steinfurth N., Sulkowski M., Tan S.-S., Tanaka J., Tashi D., Thein H.-H., Thompson P., Tolmane I., Toy M., Valantinas J., Van de Vijver D., Velez-Moller P., Vince A., Waked I., Wang S., Wedemeyer H., Wong V., Xie Q., Yamada S., Yang H.-I., Yesmembetov K., Yilmaz Y., Younossi Z., Yu M.-L., Yuen M.-F., Yurdaydin C., Yusuf A., Zekry A., Zeuzem S., Medical Microbiology & Infectious Diseases, Virology, and Negro, Francesco

Subjects
ddc:616, Carcinoma, Hepatocellular, Hepatology, Hepatitis, Viral, Human, business.industry, Liver Neoplasms, ddc:616.07, medicine.disease, World Health Organization, Virology, digestive system diseases, Goal, Infectious Diseases, Absolute (philosophy), SDG 3 - Good Health and Well-being, medicine, Humans, Viral hepatitis, business, Goals, Human
Abstract

The 69th World Health Assembly endorsed the Global Health Sector Strategy for Viral Hepatitis, embracing a goal to eliminate hepatitis infection as a public health threat by 2030. This was followed by the World Health Organization's (WHO) global targets for the care and management of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. These announcements and targets were important in raising awareness and calling for action; however, tracking countries’ progress towards these elimination goals has provided insights to the limitations of these targets. The existing targets compare a country's progress relative to its 2015 values, penalizing countries who started their programmes prior to 2015, countries with a young population, or countries with a low prevalence. We recommend that (1) WHO simplify the hepatitis elimination targets, (2) change to absolute targets and (3) allow countries to achieve these disease targets with their own service coverage initiatives that will have the maximum impact. The recommended targets are as follows: reduce HCV new chronic cases to ≤5 per 100000, reduce HBV prevalence among 1-year-olds to ≤0.1%, reduce HBV and HCV mortality to ≤5 per 100000, and demonstrate HBV and HCV year-to-year decrease in new HCV- and HBV-related HCC cases. The objective of our recommendations is not to lower expectations or diminish the hepatitis elimination standards, but to provide clearer targets that recognize the past and current elimination efforts by countries, help measure progress towards true elimination, and motivate other countries to follow suit.

Published
2021

30. Personalized surveillance for hepatocellular carcinoma in cirrhosis – using machine learning adapted to HCV status

Author

Jean-Marie Péron, Dominique Larrey, Albert Tran, Marc Bourlière, Paul Calès, Thong Dao, Eric Nguyen-Khac, Olivier Chazouillères, Brigitte Bernard-Chabert, Pierre Attali, Ghassan Riachi, Jean-Didier Grangé, Dominique Guyader, Pierre Nahon, Victor de Ledinghen, Claire Wartelle, Ariane Mallat, Christos Christidis, Christophe Pilette, Vincent Di Martino, Jean-Pierre Bronowicki, Stanislas Pol, Philippe Mathurin, Dominique Roulot, Denis Ouzan, Jean-Frédéric Blanc, Louis d’Alteroche, David Zucman, Jean-Pierre Zarski, Tarik Asselah, Etienne Audureau, Dominique Thabut, Angela Sutton, Fabien Zoulim, Laurent Alric, Carole Cagnot, Christine Silvain, Armand Abergel, Richard Layese, Fabrice Carrat, Service de santé publique [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Clinical Epidemiology and Ageing : Geriatrie Soins Primaires et Santé Publique (CEpiA), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), ANRS France Recherche Nord & sud Sida-hiv hépatites, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institut Arnault Tzanck, Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Nice (CHU Nice), Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology (U1064 Inserm - CR2TI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Hôpital Michallon, Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Agence Nationale de Recherches sur le Sida et les Hépatites Virales, Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées

Subjects
0301 basic medicine, Cirrhosis, [SDV]Life Sciences [q-bio], Machine learning, computer.software_genre, HCV clearance, 03 medical and health sciences, 0302 clinical medicine, medicine, ComputingMilieux_MISCELLANEOUS, Prothrombin time, Hepatology, medicine.diagnostic_test, business.industry, Incidence (epidemiology), Cancer, medicine.disease, digestive system diseases, 3. Good health, 030104 developmental biology, Hepatocellular carcinoma, Cohort, Screening, 030211 gastroenterology & hepatology, Artificial intelligence, Liver cancer, business, Risk assessment, computer
Abstract

Background & Aims Refining hepatocellular carcinoma (HCC) surveillance programs requires improved individual risk prediction. Thus, we aimed to develop algorithms based on machine learning approaches to predict the risk of HCC more accurately in patients with HCV-related cirrhosis, according to their virological status. Methods Patients with compensated biopsy-proven HCV-related cirrhosis from the French ANRS CO12 CirVir cohort were included in a semi-annual HCC surveillance program. Three prognostic models for HCC occurrence were built, using (i) Fine-Gray regression as a benchmark, (ii) single decision tree (DT), and (iii) random survival forest for competing risks survival (RSF). Model performance was evaluated from C-indexes validated externally in the ANRS CO22 Hepather cohort (n = 668 enrolled between 08/2012–01/2014). Results Out of 836 patients analyzed, 156 (19%) developed HCC and 434 (52%) achieved sustained virological response (SVR) (median follow-up 63 months). Fine-Gray regression models identified 6 independent predictors of HCC occurrence in patients before SVR (past excessive alcohol intake, genotype 1, elevated AFP and GGT, low platelet count and albuminemia) and 3 in patients after SVR (elevated AST, low platelet count and shorter prothrombin time). DT analysis confirmed these associations but revealed more complex interactions, yielding 8 patient groups with varying cancer risks and predictors depending on SVR achievement. On RSF analysis, the most important predictors of HCC varied by SVR status (non-SVR: platelet count, GGT, AFP and albuminemia; SVR: prothrombin time, ALT, age and platelet count). Externally validated C-indexes before/after SVR were 0.64/0.64 [Fine-Gray], 0.60/62 [DT] and 0.71/0.70 [RSF]. Conclusions Risk factors for hepatocarcinogenesis differ according to SVR status. Machine learning algorithms can refine HCC risk assessment by revealing complex interactions between cancer predictors. Such approaches could be used to develop more cost-effective tailored surveillance programs. Lay summary Patients with HCV-related cirrhosis must be included in liver cancer surveillance programs, which rely on ultrasound examination every 6 months. Hepatocellular carcinoma (HCC) screening is hampered by sensitivity issues, leading to late cancer diagnoses in a substantial number of patients. Refining surveillance periodicity and modality using more sophisticated imaging techniques such as MRI may only be cost-effective in patients with the highest HCC incidence. Herein, we demonstrate how machine learning algorithms (i.e. data-driven mathematical models to make predictions or decisions), can refine individualized risk prediction.

Published
2020

31. miRNAs as Potential Biomarkers for Viral Hepatitis B and C

Author

Stéphanie Narguet, Dimitri Loureiro, Issam Tout, Sabrina Menasria Benazzouz, Abdellah Mansouri, and Tarik Asselah

Subjects
0301 basic medicine, Liver Cirrhosis, Hepatitis B virus, Cirrhosis, diagnosis, Hepatitis C virus, lcsh:QR1-502, Inflammation, Review, Hepacivirus, chronic liver diseases, medicine.disease_cause, liver, Virus Replication, lcsh:Microbiology, 03 medical and health sciences, 0302 clinical medicine, Fibrosis, Virology, microRNA, medicine, pro-fibrogenic, Humans, business.industry, medicine.disease, Hepatitis B, Prognosis, Hepatitis C, digestive system diseases, Chronic infection, MicroRNAs, 030104 developmental biology, Infectious Diseases, anti-fibrogenic, Gene Expression Regulation, inflammation, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Immune System, Immunology, Disease Progression, chronic hepatitis, Disease Susceptibility, medicine.symptom, business, fibrosis markers, Biomarkers
Abstract

Around 257 million people are living with hepatitis B virus (HBV) chronic infection and 71 million with hepatitis C virus (HCV) chronic infection. Both HBV and HCV infections can lead to liver complications such as cirrhosis and hepatocellular carcinoma (HCC). To take care of these chronically infected patients, one strategy is to diagnose the early stage of fibrosis in order to treat them as soon as possible to decrease the risk of HCC development. microRNAs (or miRNAs) are small non-coding RNAs which regulate many cellular processes in metazoans. Their expressions were frequently modulated by up- or down-regulation during fibrosis progression. In the serum of patients with HBV chronic infection (CHB), miR-122 and miR-185 expressions are increased, while miR-29, -143, -21 and miR-223 expressions are decreased during fibrosis progression. In the serum of patients with HCV chronic infection (CHC), miR-143 and miR-223 expressions are increased, while miR-122 expression is decreased during fibrosis progression. This review aims to summarize current knowledge of principal miRNAs modulation involved in fibrosis progression during chronic hepatitis B/C infections. Furthermore, we also discuss the potential use of miRNAs as non-invasive biomarkers to diagnose fibrosis with the intention of prioritizing patients with advanced fibrosis for treatment and surveillance.

Published
2020

32. Hepatitis B surface antigen seroclearance: Immune mechanisms, clinical impact, importance for drug development

Author

Vassili Soumelis, Issam Tout, Nathalie Boyer, Abdellah Mansouri, Tarik Asselah, Dimitri Loureiro, Université Paris Cité (UPCité), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hopital Saint-Louis [AP-HP] (AP-HP), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CCSD, Accord Elsevier, Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)

Subjects
0301 basic medicine, HBsAg, [SDV]Life Sciences [q-bio], Hbsag seroclearance, Hepatitis b surface antigen, Antiviral Agents, Immune System Phenomena, 03 medical and health sciences, Hepatitis B, Chronic, 0302 clinical medicine, Immune system, Interferon, Humans, Medicine, Seroconversion, Immune mechanisms, Hepatitis B Surface Antigens, Hepatology, business.industry, virus diseases, biochemical phenomena, metabolism, and nutrition, digestive system diseases, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Drug development, Immunology, bacteria, 030211 gastroenterology & hepatology, business, medicine.drug
Abstract

HBsAg seroclearance occurs rarely in the natural history of chronic hepatitis B (CHB) infection and is associated with improved clinical outcomes. Many factors are associated with HBsAg seroconversion, including immune and viral factors. However, the immune mechanisms associated with HBsAg seroclearance are still difficult to elucidate. HBsAg seroclearance is the ideal aim of HBV treatment. Unfortunately, this goal is rarely achieved with current treatments. Understanding the mechanisms of HBsAg loss appears to be important for the development of curative HBV treatments. While studies from animal models give insights into the potential immune mechanisms and interactions occurring between the immune system and HBsAg, they do not recapitulate all features of CHB in humans and are subject to variability due to their complexity. In this article, we review recent studies on these immune factors, focusing on their influence on CHB progression and HBsAg seroconversion. These data provide new insights for the development of therapeutic approaches to partially restore the anti-HBV immune response. Targeting HBsAg will ideally relieve the immunosuppressive effects on the immune system and help to restore anti-HBV immune responses.

Published
2020

33. Phase 3, Multicenter Open‐Label study to investigate the efficacy of elbasvir and grazoprevir fixed‐dose combination for 8 weeks in treatment‐naïve, HCV GT1b‐infected patients, with non‐severe fibrosis

Author

Véronique Loustaud-Ratti, Armand Abergel, Nicolas Andant, A. Mallat, Marie Dodel, Isabelle Fouchard-Hubert, Stanislas Pol, Maud Reymond, Brigitte Chanteranne, Bruno Pereira, François Bailly, Dominique Larrey, Albert Tran, Didier Samuel, Frederic Faure, Vincent Di Martino, J. Gournay, Benjamin Buchard, Tarik Asselah, Géraldine Lamblin, Leon Muti, Camille Teilhet, Service d'Hépatologie Gastro-entérologie [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de recherche Maladies Métaboliques et Micronutriments (U3M), Institut National de la Recherche Agronomique (INRA), Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Maladies de l’Appareil Digestif [CHU Nantes], Université de Limoges (UNILIM), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), and Université d'Angers (UA)

Subjects
Adult, Cyclopropanes, Male, medicine.medical_specialty, Elbasvir, Asia, Genotype, [SDV]Life Sciences [q-bio], Fixed-dose combination, Hepacivirus, Antiviral Agents, Gastroenterology, Therapy naive, 03 medical and health sciences, 0302 clinical medicine, Fibrosis, Quinoxalines, Internal medicine, Ribavirin, medicine, Clinical endpoint, Humans, ComputingMilieux_MISCELLANEOUS, Aged, Benzofurans, Sulfonamides, Hepatology, business.industry, Imidazoles, Middle Aged, medicine.disease, Amides, Hepatitis C, 3. Good health, Europe, Grazoprevir, 030220 oncology & carcinogenesis, Drug Therapy, Combination, Female, 030211 gastroenterology & hepatology, Carbamates, business, Viral load
Abstract

BACKGROUND Genotype 1b is the most common HCV genotype worldwide, accounting for the largest proportion of infections in Europe, Russia, Latin America and Asia. Reducing treatment duration can improve adherence, reduce drug exposure and cost. Accordingly, we evaluated the efficacy of 8 weeks fixed-dose combination of grazoprevir-elbasvir in treatment-naive patients, with non-severe fibrosis. METHODS HCV mono-infected and treatment naive patients with non-severe fibrosis (Fibroscan®

Published
2020

34. Efficacy and safety of elbasvir/grazoprevir for 8 or 12 weeks for hepatitis C virus genotype 4 infection: A randomized study

Author

George J. Hanna, Laurent Alric, Vincent Leroy, Stanislas Pol, Dominique Larrey, Barbara Haber, Tarik Asselah, Michael N. Robertson, Christophe Hézode, Ernest Asante-Appiah, Deborah D. Brown, Feng-Hsiu Su, Véronique Loustaud-Ratti, Lawrence Serfaty, Eric Nguyen-Khac, Peggy Hwang, Jessie Durrand Hall, Jean-Pierre Bronowicki, Amir Guidoum, Albert Tran, Violaine Ozenne, Rohit Talwani, Si Nafa Si Ahmed, Karin Hagen, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'hépatologie médicale [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Biomécanique cellulaire et respiratoire (BCR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation (IPPRITT), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CRHU Nancy, Hôpital Saint-Éloi [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), CHU Toulouse [Toulouse], Groupe de Recherche sur l'alcool et les pharmacodépendances - UMR INSERM_S 1247 (GRAP), Université de Picardie Jules Verne (UPJV)-Institut National de la Santé et de la Recherche Médicale (INSERM), Whitehouse Station, Centre de Recherche Saint-Antoine (CRSA), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)

Subjects
Cyclopropanes, medicine.medical_specialty, Elbasvir, Genotype, [SDV]Life Sciences [q-bio], Hepacivirus, Antiviral Agents, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Quinoxalines, Internal medicine, medicine, Clinical endpoint, Humans, Elbasvir, Grazoprevir, Adverse effect, Benzofurans, Sulfonamides, Hepatology, business.industry, Imidazoles, Hepatitis C, Hepatitis C, Chronic, medicine.disease, Amides, Regimen, Grazoprevir, 030220 oncology & carcinogenesis, Drug Therapy, Combination, Egypt, 030211 gastroenterology & hepatology, Carbamates, France, business
Abstract

International audience; Background & Aims Hepatitis C virus (HCV) genotype (GT) 4 infection is prevalent in sub-Saharan Africa and the Middle East, particularly in Egypt. This study evaluated the safety and efficacy of elbasvir/grazoprevir administered for 8 and 12 weeks in participants with HCV GT4 infection. Methods In this partially randomized, open-label multicentre study conducted in France (NCT03111108; Protocol MK5172-096), treatment-naive participants with GT4 infection and F0-F2 fibrosis were randomized 2:1 to elbasvir (50 mg)/grazoprevir (100 mg) for 8 or 12 weeks. Treatment-naive participants with F3-F4 fibrosis and all treatment-experienced participants (F0-F4) were assigned to elbasvir/grazoprevir for 12 weeks. The primary endpoint was sustained virologic response (SVR) 12 weeks after the end of therapy. Results One hundred and seventeen participants were enrolled. Among treatment-naive participants with F0-F2 fibrosis, SVR was achieved by 94% (50/53) and 96% (26/27) of those receiving elbasvir/grazoprevir for 8 or 12 weeks, respectively, and four participants relapsed. In the 12-week arm, 95% (35/37) achieved SVR and two participants relapsed. NS5A resistance-associated substitutions were present at baseline and virologic failure in five of the participants with relapse. Drug-related adverse events occurred in 42% (n = 22) and 50% (n = 32) of participants receiving 8 and 12 weeks of treatment, respectively. No participant discontinued treatment owing to an adverse event. Conclusion These data confirm the efficacy of elbasvir/grazoprevir administered for 12 weeks in treatment-experienced individuals with HCV GT4 infection and those with advanced fibrosis. Treatment-naive individuals with mild fibrosis can be treated effectively with an 8-week regimen.

Published
2020

35. Adherence to pan‐genotypic glecaprevir/pibrentasvir and efficacy in HCV‐infected patients: A pooled analysis of clinical trials

Author

Brian Conway, Yaozhu J. Chen, Jason Grebely, Tania M. Welzel, Ashley Brown, Henning Kleine, Alessio Aghemo, Yang Lei, Francesco Negro, David Pugatch, Eric Lawitz, Tarik Asselah, Federico J. Mensa, Norbert Bräu, Massimo Puoti, and Liu, Chun‐Jen

Subjects
hepatitis C virus, Cyclopropanes, medicine.medical_specialty, Aminoisobutyric Acids, Pyrrolidines, Genotype, Proline, Hepatitis C virus, Viral Hepatitis, Lactams, Macrocyclic, Population, pibrentasvir, Hepacivirus, ddc:616.07, Logistic regression, medicine.disease_cause, Antiviral Agents, 03 medical and health sciences, 0302 clinical medicine, Leucine, Internal medicine, Quinoxalines, Medicine, Humans, adherence, ddc:610, education, education.field_of_study, Sulfonamides, Hepatology, business.industry, Pibrentasvir, Glecaprevir, glecaprevir, Hepatitis C, Chronic, Hepatitis C, Clinical trial, Adherence, 030220 oncology & carcinogenesis, Pill, 030211 gastroenterology & hepatology, Original Article, Benzimidazoles, G/P, business
Abstract

Background & aims Adequate adherence to hepatitis C virus (HCV) treatment is believed to be a key component of treatment success because non-adherence can potentially result in treatment failure and the emergence of resistant viral variants. This analysis assessed factors associated with non-adherence to glecaprevir/pibrentasvir (G/P) therapy and the impact of non-adherence on sustained virological response at post-treatment week 12 (SVR12) rates in HCV genotype (GT) 1-6-infected patients. Methods Adherence was calculated by pill counts at study visits during treatment, and defined as having a lowest treatment adherence of ≥80% and ≤120% at each study visit. Exploratory logistic regression modelling assessed predictors of non-adherence to G/P therapy. SVR12 rates by treatment adherence were assessed in the intent-to-treat (ITT) population and modified ITT (mITT) population, which excludes non-virological failures. Results Overall, 97% (2024/2091) of patients were adherent to G/P therapy at all consecutive study visits. Alcohol use was the only baseline characteristic independently associated with non-adherence to G/P therapy (OR: 2.38; 95% CI: 1.13-5.01; P = .022). In the mITT population, overall SVR12 rates were high both in patients who were adherent to G/P therapy and those who were not (99% [1983/2008] and 95% [58/61] respectively; P = .047). Corresponding SVR12 rates in the ITT population were 98% (1983/2024) and 87% (58/67) respectively. Conclusions Most patients adhered to G/P therapy. SVR12 rates were high both in patients who were adherent to G/P treatment and those who were not. Patient education on treatment adherence should remain an important part of HCV treatment. Clinical trials registration NCT02604017, NCT02640482, NCT02640157, NCT02636595, NCT02642432, NCT02651194, NCT02243293, NCT02446717.

Published
2019

36. Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment a prospective cohort study

Author

Albert Tran, Victor de Ledinghen, Armand Abergel, Céline Dorival, Olivier Chazouillères, Louis d’Alteroche, Isabelle Rosa, Didier Samuel, Moana Gelu-Simeon, Laurent Alric, Vincent Leroy, Jérôme Gournay, François Habersetzer, Dominique Guyader, Stanislas Pol, Véronique Loustaud-Ratti, Ghassan Riachi, Jean-Pierre Bronowicki, Hélène Fontaine, Anne Minello, Christophe Hézode, Philippe Mathurin, Claire Geist, Nathalie Ganne, Mélanie Simony, Dominique Thabut, François Raffi, Xavier Causse, Patrick Marcellin, Sophie Metivier, Paul Calès, Isabelle Portal, Marc Bourlière, Dominique Larrey, Fabien Zoulim, Fabrice Carrat, Alpha Diallo, Georges Haour, Tarik Asselah, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département d'hépatologie [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANRS France Recherche Nord & sud Sida-hiv hépatites, Biomécanique cellulaire et respiratoire (BCR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie du cancer du foie, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre Hospitalier Universitaire de Nice (CHU Nice), Interactions Virus-Hôte et Maladies Hépatiques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Virologie, Physiopathologie et traitement des maladies du foie, Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU), Physiopathologie des Maladies Inflammatoires de l'Intestin, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Rouen, Normandie Université (NU), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Image Science for Interventional Techniques (ISIT), Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université-Centre National de la Recherche Scientifique (CNRS), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation (IPPRITT), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Régional d'Orléans (CHRO), Service d'Hépato-gastro-entérologie [CHR Metz-Thionville], Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), Equipe EPICAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Hospitalier Intercommunal de Créteil (CHIC), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Aix Marseille Université (AMU), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'hépatologie et de gastroentérologie [Hôpital Saint-Joseph - Marseille], Aix Marseille Université (AMU)-Hôpital Saint-Joseph [Marseille], Physiopathologie du système immunitaire (Inserm U1223), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU Toulouse [Toulouse], Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], CCSD, Accord Elsevier, Institut National de la Recherche Agronomique (INRA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bordeaux Segalen - Bordeaux 2, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), and Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)

Subjects
Adult, Liver Cirrhosis, Male, medicine.medical_specialty, Carcinoma, Hepatocellular, Cirrhosis, medicine.medical_treatment, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, Liver transplantation, Antiviral Agents, Gastroenterology, 03 medical and health sciences, Liver disease, Viewpoint, 0302 clinical medicine, Internal medicine, medicine, Humans, Prospective Studies, 030212 general & internal medicine, Prospective cohort study, Aged, Proportional Hazards Models, business.industry, Incidence, Liver Neoplasms, Hazard ratio, General Medicine, Hepatitis C, Hepatitis C, Chronic, Middle Aged, Hepatology, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], Treatment Outcome, Hepatocellular carcinoma, Female, France, business
Abstract

Although direct-acting antivirals have been used extensively to treat patients with chronic hepatitis C virus (HCV) infection, their clinical effectiveness has not been well reported. We compared the incidence of death, hepatocellular carcinoma, and decompensated cirrhosis between patients treated with direct-acting antivirals and those untreated, in the French ANRS CO22 Hepather cohort.We did a prospective study in adult patients with chronic HCV infection enrolled from 32 expert hepatology centres in France. We excluded patients with chronic hepatitis B, those with a history of decompensated cirrhosis, hepatocellular carcinoma, or liver transplantation, and patients who were treated with interferon-ribavirin with or without first-generation protease inhibitors. Co-primary study outcomes were incidence of all-cause mortality, hepatocellular carcinoma, and decompensated cirrhosis. The association between direct-acting antivirals and these outcomes was quantified using time-dependent Cox proportional hazards models. This study is registered with ClinicalTrials.gov, number NCT01953458.Between Aug 6, 2012, and Dec 31, 2015, 10 166 patients were eligible for the study. 9895 (97%) patients had available follow-up information and were included in analyses. Median follow-up was 33·4 months (IQR 24·0-40·7). Treatment with direct-acting antivirals was initiated during follow-up in 7344 patients, and 2551 patients remained untreated at the final follow-up visit. During follow-up, 218 patients died (129 treated, 89 untreated), 258 reported hepatocellular carcinoma (187 treated, 71 untreated), and 106 had decompensated cirrhosis (74 treated, 32 untreated). Exposure to direct-acting antivirals was associated with increased risk for hepatocellular carcinoma (unadjusted hazard ratio [HR] 2·77, 95% CI 2·07-3·71) and decompensated cirrhosis (3·83, 2·29-6·42). After adjustment for variables (age, sex, body-mass index, geographical origin, infection route, fibrosis score, HCV treatment-naive, HCV genotype, alcohol consumption, diabetes, arterial hypertension, biological variables, and model for end-stage liver disease score in patients with cirrhosis), exposure to direct-acting antivirals was associated with a decrease in all-cause mortality (adjusted HR 0·48, 95% CI 0·33-0·70) and hepatocellular carcinoma (0·66, 0·46-0·93), and was not associated with decompensated cirrhosis (1·14, 0·57-2·27).Treatment with direct-acting antivirals is associated with reduced risk for mortality and hepatocellular carcinoma and should be considered in all patients with chronic HCV infection.INSERM-ANRS (France Recherche NordSud Sida-HIV Hépatites), ANR (Agence Nationale de la Recherche), DGS (Direction Générale de la Santé), MSD, Janssen, Gilead, AbbVie, Bristol-Myers Squibb, and Roche.

Published
2019

37. Identification of 19 Novel Hepatitis C Virus Subtypes—Further Expanding HCV Classification

Author

Jyh Jou Chen, Charlotte Hedskog, Stephen D. Shafran, Jane Collier, Armando Abergel, Bandita Parhy, Christophe Moreno, Peter Simmonds, Sergio Borgia, Stefan Zeuzem, Laurent Alric, Robert H. Hyland, Evguenia S. Svarovskaia, Hongmei Mo, Tarik Asselah, Dharmesh Kapoor, and Silvia Chang

Subjects
0301 basic medicine, Sofosbuvir, Hepatitis C virus, Voxilaprevir, medicine.disease_cause, sofosbuvir, Major Articles, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Genotype, medicine, ddc:610, NS5A, NS5B, Velpatasvir, Genetic diversity, NS3, Phylogenetic analysis, business.industry, phylogenetic analysis, velpatasvir, virus diseases, Généralités, voxilaprevir, Virology, digestive system diseases, Resistance-associated substitutions (RAS), 030104 developmental biology, Infectious Diseases, Oncology, chemistry, resistance-associated substitutions (RAS), direct-acting antivirals (DAAs), 030211 gastroenterology & hepatology, Direct-acting antivirals (DAAs), business, medicine.drug
Abstract

Background. Hepatitis C virus (HCV) is currently classified into 8 genotypes and 86 subtypes. The objective of this study was to characterize novel HCV subtypes and to investigate the impact of subtypes on treatment outcome. Methods. Full-genome sequencing was performed on HCV plasma samples with, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2019

38. SAT-490-No Impact of Direct-Acting Antivirals on Recurrent Hepatocellular Carcinoma Tumour Growth in the ANRS CO22 Hepather Cohort

Author

Tarik Asselah, Pol Stanislas, Fabien Zoulim, Isabelle Rosa, A.V. Pichard, Hélène Fontaine, Olivier Chazouillères, Correas Jean Michel, Dominique Larrey, Marc Bourlière, Nathalie Ganne, Véronique Loustaud-Ratti, Jérôme Gournay, Philippe Mathurin, Vincent Leroy, Albert Tran, Jean-Pierre Bronowicki, Didier Samuel, Dorival Celine, Dominique Guyader, Paul Calès, Christophe Hézode, Metivier Sophie, Victor de Ledinghen, Fabrice Carrat, Département d'hépatologie [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hospices Civils de Lyon, Departement de Neurologie (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Lille, Épidémiologie clinique des maladies virales chroniques [iPLesp] (CLEPIVIR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Physiopathologie du système immunitaire (Inserm U1223), and Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)

Subjects
Oncology, medicine.medical_specialty, Hepatology, business.industry, Internal medicine, [SDV]Life Sciences [q-bio], Cohort, Medicine, business, DIRECT ACTING ANTIVIRALS, Recurrent Hepatocellular Carcinoma
Abstract

International audience

Published
2019

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

Author

Zobair M Younossi, Vlad Ratziu, Rohit Loomba, Mary Rinella, Quentin M Anstee, Zachary Goodman, Pierre Bedossa, Andreas Geier, Susanne Beckebaum, Philip N Newsome, David Sheridan, Muhammad Y Sheikh, James Trotter, Whitfield Knapple, Eric Lawitz, Manal F Abdelmalek, Kris V Kowdley, Aldo J Montano-Loza, Jerome Boursier, Philippe Mathurin, Elisabetta Bugianesi, Giuseppe Mazzella, Antonio Olveira, Helena Cortez-Pinto, Isabel Graupera, David Orr, Lise Lotte Gluud, Jean-Francois Dufour, David Shapiro, Jason Campagna, Luna Zaru, Leigh MacConell, Reshma Shringarpure, Stephen Harrison, Arun J Sanyal, Manal Abdelmalek, Gary Abrams, Humberto Aguilar, Aijaz Ahmed, Elmar Aigner, Guruprasad Aithal, Aftab Ala, William Alazawi, Agustin Albillos, Michael Allison, Sfa Al-Shamma, Raul Andrade, Pietro Andreone, Mario Angelico, Victor Ankoma-Sey, Quentin Anstee, Rodolphe Anty, Victor Araya, Juan Ignacio Arenas Ruiz, Perttu Arkkila, Marty Arora, Tarik Asselah, Jennifer Au, Oyekoya Ayonrinde, Robert James Bailey, Maya Balakrishnan, Kiran Bambha, Meena Bansal, Sidney Barritt, John Bate, Jorge Beato, Jaideep Behari, Pablo Bellot, Ziv Ben Ari, Michael Bennett, Marina Berenguer, Benedetta Terziroli Beretta-Piccoli, Thomas Berg, Maurizio Bonacini, Lucia Bonet, Brian Borg, Marc Bourliere, William Bowman, David Bradley, Marija Brankovic, Marius Braun, Jean-Pierre Bronowicki, Savino Bruno, Cindy Cai, Amy Calderon, José Luis Calleja Panero, Elizabeth Carey, Michal Carmiel, Jose Antonio Carrión, Matthew Cave, Cristina Chagas, Tawfik Chami, Alan Chang, Allan Coates, Jeremy Cobbold, Charlote Costentin, Kathleen Corey, Lynsey Corless, Javier Crespo, Oscar Cruz Pereira, Victor de Ledinghen, Andrew deLemos, Moises Diago, Mamie Dong, Jean-François Dufour, Predrag Dugalic, Winston Dunn, Magby Elkhashab, Michael Epstein, Maria Desamparados Escudero-Garcia, Ohad Etzion, Larry Evans, Robert Falcone, Conrado Fernandez, Jose Ferreira, Scott Fink, Kevin Finnegan, Roberto Firpi-Morell, Annarosa Floreani, Thierry Fontanges, Ryan Ford, Ewan Forrest, Andrew Fowell, Anna Ludovica Fracanzani, Sven Francque, Bradley Freilich, Juan Frias, Michael Fuchs, Javier Fuentes, Michael Galambos, Juan Gallegos, Anja Geerts, Jacob George, Maged Ghali, Reem Ghalib, Pierre Gholam, Pere Gines, Norman Gitlin, Tobias Goeser, John Goff, Stuart Gordon, Frederic Gordon, Odile Goria, Shaun Greer, Alla Grigorian, Henning Gronbaek, Maeva Guillaume, Naresh Gunaratnam, Dina Halegoua-De Marzio, Bilal Hameed, Stephanie Hametner, James Hamilton, Marek Hartleb, Tarek Hassanein, Dieter Häussinger, Paul Hellstern, Robert Herring, Eva Heurich, Christophe Hezode, Holger Hinrichsen, Peter Holland Fischer, Yves Horsmans, Jonathan Huang, Hyder Hussaini, Antoine Jakiche, Lennox Jeffers, Blake Jones, Rosa Jorge, Francisco Jorquera, Shoba Joshi, Alisan Kahraman, Kelly Kaita, Nicholas Karyotakis, Zeid Kayali, Stergios Kechagias, Thomas Kepczyk, Mandana Khalili, Hicham Khallafi, Johannes Kluwe, Anita Kohli, Kevin Korenblat, Kris Kowdley, Aleksander Krag, Richard Krause, Andreas Kremer, Karen Krok, Miodrag Krstic, Marcelo Kugelmas, Sonal Kumar, Scott Kuwada, Damien Labarriere, Michelle Lai, Wim Laleman, Pietro Lampertico, Alice Lee, Vincent Leroy, Steven Lidofsky, Tina Huey Lim, Joseph Lim, Donald Lipkis, Ester Little, Amadeo Lonardo, Michelle Long, Velimir Anthony Christopher Luketic, Yoav Lurie, Guilherme Macedo, Joana Magalhaes, Mihály Makara, Benedict Maliakkal, Michael Manns, Pinelopi Manousou, Parvez Mantry, Giulio Marchesini, Carla Marinho, Paul Marotta, Hanns-Ulrich Marschall, Linda Martinez, Marlyn Mayo, Mark McCullen, William McLaughlin, Uta Merle, Raphael Merriman, Apurva Modi, Esther Molina, Aldo Montano-Loza, Carlos Monteverde, Amilcar Morales Cardona, Sulleman Moreea, Christophe Moreno, Filomena Morisco, Abdullah Mubarak, Beat Muellhaupt, Sandeep Mukherjee, Tobias Müller, Aleksandar Nagorni, Jahnavi Naik, Guy Neff, Moises Nevah, Philip Newsome, Eric Nguyen-Khac, Mazen Noureddin, Jude Oben, Hans Orlent, James Orr, Grisell Ortiz-Lasanta, Violaine Ozenne, Prashant Pandya, Angelo Paredes, James Park, Joykumar Patel, Keyur Patel, Sonali Paul, Heather Patton, Markus Peck-Radosavljevic, Salvatore Petta, Stephen Pianko, Anna Piekarska, Neville Pimstone, Joseph Pisegna, Paul Pockros, Stanislas Pol, Michael Porayko, John Poulos, David Pound, Joe Pouzar, Jose Presa Ramos, Nikolaos Pyrsopoulos, Nila Rafiq, Kate Muller, Alnoor Ramji, Ravi Ravinuthala, Chakradhar Reddy, Gautham Reddy K G, K. Rajender Reddy K R, Frederic Regenstein, Robert Reindollar, Justin Reynolds, Andres Riera, Jose Rivera Acosta, Geert Robaeys, Stuart Roberts, Federico Rodriguez-Perez, Sandor Romero, Manuel Romero-Gomez, Raymond Rubin, Mariagrazia Rumi, Simon Rushbrook, Christian Rust, Michael Ryan, Rifaat Safadi, Adnan Said, Kimmo Salminen, Didier Samuel, John Santoro, Arun Sanyal, Souvik Sarkar, Cynthia Schaeffer, Jörn Schattenberg, Ingolf Schiefke, Eugene Schiff, Wolfgang Schmidt, Jeffrey Schneider, Jeoffrey Schouten, Michael Schultz, Giada Sebastiani, David Semela, Thomas Sepe, Aasim Sheikh, Muhammad Sheikh, Kenneth Sherman, Oren Shibolet, Mitchell Shiffman, Asma Siddique, Cyril Sieberhagen, Samuel Sigal, Katarzyna Sikorska, Krzysztof Simon, Marie Sinclair, Richard Skoien, Joel Solis, Siddharth Sood, Bob Souder, James Spivey, Per Stal, Laura Stinton, Simone Strasser, Petar Svorcan, Gyongzi Szabo, Andrew Talal, Edward Tam, Brent Tetri, Paul Thuluvath, Hillel Tobias, Krzysztof Tomasiewicz, Dawn Torres, Albert Tran, Michael Trauner, Christian Trautwein, Emanuel Tsochatzis, Esther Unitt, Victor Vargas, Istvan Varkonyi, Ella Veitsman, Umberto Vespasiani Gentilucci, David Victor, John Vierling, Catherine Vincent, Aron Vincze, Manfred von der Ohe, Natasha Von Roenn, Raj Vuppalanchi, Michael Waters, Kymberly Watt, Julia Wattacheril, Martin Weltman, Amanda Wieland, Gregory Wiener, Alonzo Williams A, Jeffrey Williams J, Jason Wilson, Maria Yataco, Eric Yoshida, Ziad Younes, Liyun Yuan, Adam Zivony, Donald Zogg, Heinz Zoller, Fabien Zoulim, Eli Zuckerman, Massimo Zuin, Younossi Z.M., Ratziu V., Loomba R., Rinella M., Anstee Q.M., Goodman Z., Bedossa P., Geier A., Beckebaum S., Newsome P.N., Sheridan D., Sheikh M.Y., Trotter J., Knapple W., Lawitz E., Abdelmalek M.F., Kowdley K.V., Montano-Loza A.J., Boursier J., Mathurin P., Bugianesi E., Mazzella G., Olveira A., Cortez-Pinto H., Graupera I., Orr D., Gluud L.L., Dufour J.-F., Shapiro D., Campagna J., Zaru L., MacConell L., Shringarpure R., Harrison S., Sanyal A.J., Abdelmalek M., Abrams G., Aguilar H., Ahmed A., Aigner E., Aithal G., Ala A., Alazawi W., Albillos A., Allison M., Al-Shamma S., Andrade R., Andreone P., Angelico M., Ankoma-Sey V., Anstee Q., Anty R., Araya V., Arenas Ruiz J.I., Arkkila P., Arora M., Asselah T., Au J., Ayonrinde O., Bailey R.J., Balakrishnan M., Bambha K., Bansal M., Barritt S., Bate J., Beato J., Behari J., Bellot P., Ben Ari Z., Bennett M., Berenguer M., Beretta-Piccoli B.T., Berg T., Bonacini M., Bonet L., Borg B., Bourliere M., Bowman W., Bradley D., Brankovic M., Braun M., Bronowicki J.-P., Bruno S., Cai C., Calleja Panero J.L., Carey E., Carmiel M., Carrion J.A., Cave M., Chagas C., Chami T., Chang A., Coates A., Cobbold J., Corey K., Corless L., Crespo J., Cruz Pereira O., de Ledinghen V., deLemos A., Diago M., Dugalic P., Dunn W., Elkhashab M., Epstein M., Escudero-Garcia M.D., Etzion O., Evans L., Falcone R., Fernandez C., Ferreira J., Fink S., Finnegan K., Firpi-Morell R., Floreani A., Fontanges T., Ford R., Forrest E., Fowell A., Fracanzani A.L., Francque S., Freilich B., Frias J., Fuchs M., Fuentes J., Galambos M., Gallegos J., Geerts A., George J., Ghali M., Ghalib R., Gholam P., Gines P., Gitlin N., Goeser T., Goff J., Gordon S., Gordon F., Goria O., Greer S., Grigorian A., Gronbaek H., Guillaume M., Gunaratnam N., Halegoua-De Marzio D., Hameed B., Hametner S., Hamilton J., Hartleb M., Hassanein T., Haussinger D., Hellstern P., Herring R., Heurich E., Hezode C., Hinrichsen H., Holland Fischer P., Horsmans Y., Huang J., Jakiche A., Jeffers L., Jones B., Jorge R., Jorquera F., Kahraman A., Kaita K., Karyotakis N., Kayali Z., Kechagias S., Kepczyk T., Khalili M., Khallafi H., Kluwe J., Kohli A., Korenblat K., Kowdley K., Krag A., Krause R., Kremer A., Krok K., Krstic M., Kugelmas M., Kumar S., Labarriere D., Lai M., Lampertico P., Lee A., Leroy V., Lidofsky S., Lim T.H., Lim J., Lipkis D., Little E., Lonardo A., Long M., Lurie Y., Macedo G., Makara M., Maliakkal B., Manns M., Manousou P., Mantry P., Marchesini G., Marinho C., Marotta P., Marschall H.-U., Mayo M., McCullen M., McLaughlin W., Merriman R., Modi A., Molina E., Montano-Loza A., Monteverde C., Moreea S., Moreno C., Morisco F., Mubarak A., Muellhaupt B., Mukherjee S., Muller T., Nagorni A., Naik J., Neff G., Nevah M., Newsome P., Nguyen-Khac E., Noureddin M., Oben J., Orlent H., Orr J., Ortiz-Lasanta G., Ozenne V., Pandya P., Paredes A., Park J., Patel J., Patel K., Uta M., Patton H., Peck-Radosavljevic M., Petta S., Pianko S., Piekarska A., Pimstone N., Pockros P., Pol S., Porayko M., Poulos J., Pound D., Pouzar J., Presa Ramos J., Pyrsopoulos N., Rafiq N., Muller K., Ramji A., Ravinuthala R., Reddy C., Reddy K G G., Reddy K R K.R., Regenstein F., Reindollar R., Riera A., Rivera Acosta J., Robaeys G., Roberts S., Rodriguez-Perez F., Romero-Gomez M., Rubin R., Rumi M., Rushbrook S., Rust C., Ryan M., Safadi R., Said A., Salminen K., Samuel D., Santoro J., Sanyal A., Sarkar S., Schaeffer C., Schattenberg J., Schiefke I., Schiff E., Schmidt W., Schneider J., Schouten J., Schultz M., Sebastiani G., Semela D., Sepe T., Sheikh A., Sheikh M., Sherman K., Shibolet O., Shiffman M., Siddique A., Sieberhagen C., Sigal S., Sikorska K., Simon K., Sinclair M., Skoien R., Solis J., Sood S., Souder B., Spivey J., Stal P., Stinton L., Strasser S., Svorcan P., Szabo G., Talal A., Tam E., Tetri B., Thuluvath P., Tobias H., Tomasiewicz K., Torres D., Trauner M., Trautwein C., Tsochatzis E., Unitt E., Vargas V., Varkonyi I., Veitsman E., Vespasiani Gentilucci U., Victor D., Vierling J., Vincent C., Vincze A., von der Ohe M., Von Roenn N., Vuppalanchi R., Waters M., Watt K., Weltman M., Wieland A., Wiener G., Williams A A., Williams J J., Wilson J., Yataco M., Yoshida E., Younes Z., Yuan L., Zivony A., Zogg D., Zoller H., Zoulim F., Zuckerman E., Zuin M., Repositório da Universidade de Lisboa, Younossi, Z. M., Ratziu, V., Loomba, R., Rinella, M., Anstee, Q. M., Goodman, Z., Bedossa, P., Geier, A., Beckebaum, S., Newsome, P. N., Sheridan, D., Sheikh, M. Y., Trotter, J., Knapple, W., Lawitz, E., Abdelmalek, M. F., Kowdley, K. V., Montano-Loza, A. J., Boursier, J., Mathurin, P., Bugianesi, E., Mazzella, G., Olveira, A., Cortez-Pinto, H., Graupera, I., Orr, D., Gluud, L. L., Dufour, J. -F., Shapiro, D., Campagna, J., Zaru, L., Macconell, L., Shringarpure, R., Harrison, S., Sanyal, A. J., Abdelmalek, M., Abrams, G., Aguilar, H., Ahmed, A., Aigner, E., Aithal, G., Ala, A., Alazawi, W., Albillos, A., Allison, M., Al-Shamma, S., Andrade, R., Andreone, P., Angelico, M., Ankoma-Sey, V., Anstee, Q., Anty, R., Araya, V., Arenas Ruiz, J. I., Arkkila, P., Arora, M., Asselah, T., Au, J., Ayonrinde, O., Bailey, R. J., Balakrishnan, M., Bambha, K., Bansal, M., Barritt, S., Bate, J., Beato, J., Behari, J., Bellot, P., Ben Ari, Z., Bennett, M., Berenguer, M., Beretta-Piccoli, B. T., Berg, T., Bonacini, M., Bonet, L., Borg, B., Bourliere, M., Bowman, W., Bradley, D., Brankovic, M., Braun, M., Bronowicki, J. -P., Bruno, S., Cai, C., Calleja Panero, J. L., Carey, E., Carmiel, M., Carrion, J. A., Cave, M., Chagas, C., Chami, T., Chang, A., Coates, A., Cobbold, J., Corey, K., Corless, L., Crespo, J., Cruz Pereira, O., de Ledinghen, V., Delemos, A., Diago, M., Dugalic, P., Dunn, W., Elkhashab, M., Epstein, M., Escudero-Garcia, M. D., Etzion, O., Evans, L., Falcone, R., Fernandez, C., Ferreira, J., Fink, S., Finnegan, K., Firpi-Morell, R., Floreani, A., Fontanges, T., Ford, R., Forrest, E., Fowell, A., Fracanzani, A. L., Francque, S., Freilich, B., Frias, J., Fuchs, M., Fuentes, J., Galambos, M., Gallegos, J., Geerts, A., George, J., Ghali, M., Ghalib, R., Gholam, P., Gines, P., Gitlin, N., Goeser, T., Goff, J., Gordon, S., Gordon, F., Goria, O., Greer, S., Grigorian, A., Gronbaek, H., Guillaume, M., Gunaratnam, N., Halegoua-De Marzio, D., Hameed, B., Hametner, S., Hamilton, J., Hartleb, M., Hassanein, T., Haussinger, D., Hellstern, P., Herring, R., Heurich, E., Hezode, C., Hinrichsen, H., Holland Fischer, P., Horsmans, Y., Huang, J., Jakiche, A., Jeffers, L., Jones, B., Jorge, R., Jorquera, F., Kahraman, A., Kaita, K., Karyotakis, N., Kayali, Z., Kechagias, S., Kepczyk, T., Khalili, M., Khallafi, H., Kluwe, J., Kohli, A., Korenblat, K., Kowdley, K., Krag, A., Krause, R., Kremer, A., Krok, K., Krstic, M., Kugelmas, M., Kumar, S., Labarriere, D., Lai, M., Lampertico, P., Lee, A., Leroy, V., Lidofsky, S., Lim, T. H., Lim, J., Lipkis, D., Little, E., Lonardo, A., Long, M., Lurie, Y., Macedo, G., Makara, M., Maliakkal, B., Manns, M., Manousou, P., Mantry, P., Marchesini, G., Marinho, C., Marotta, P., Marschall, H. -U., Mayo, M., Mccullen, M., Mclaughlin, W., Merriman, R., Modi, A., Molina, E., Montano-Loza, A., Monteverde, C., Moreea, S., Moreno, C., Morisco, F., Mubarak, A., Muellhaupt, B., Mukherjee, S., Muller, T., Nagorni, A., Naik, J., Neff, G., Nevah, M., Newsome, P., Nguyen-Khac, E., Noureddin, M., Oben, J., Orlent, H., Orr, J., Ortiz-Lasanta, G., Ozenne, V., Pandya, P., Paredes, A., Park, J., Patel, J., Patel, K., Uta, M., Patton, H., Peck-Radosavljevic, M., Petta, S., Pianko, S., Piekarska, A., Pimstone, N., Pockros, P., Pol, S., Porayko, M., Poulos, J., Pound, D., Pouzar, J., Presa Ramos, J., Pyrsopoulos, N., Rafiq, N., Muller, K., Ramji, A., Ravinuthala, R., Reddy, C., Reddy K G, G., Reddy K R, K. R., Regenstein, F., Reindollar, R., Riera, A., Rivera Acosta, J., Robaeys, G., Roberts, S., Rodriguez-Perez, F., Romero-Gomez, M., Rubin, R., Rumi, M., Rushbrook, S., Rust, C., Ryan, M., Safadi, R., Said, A., Salminen, K., Samuel, D., Santoro, J., Sanyal, A., Sarkar, S., Schaeffer, C., Schattenberg, J., Schiefke, I., Schiff, E., Schmidt, W., Schneider, J., Schouten, J., Schultz, M., Sebastiani, G., Semela, D., Sepe, T., Sheikh, A., Sheikh, M., Sherman, K., Shibolet, O., Shiffman, M., Siddique, A., Sieberhagen, C., Sigal, S., Sikorska, K., Simon, K., Sinclair, M., Skoien, R., Solis, J., Sood, S., Souder, B., Spivey, J., Stal, P., Stinton, L., Strasser, S., Svorcan, P., Szabo, G., Talal, A., Tam, E., Tetri, B., Thuluvath, P., Tobias, H., Tomasiewicz, K., Torres, D., Trauner, M., Trautwein, C., Tsochatzis, E., Unitt, E., Vargas, V., Varkonyi, I., Veitsman, E., Vespasiani Gentilucci, U., Victor, D., Vierling, J., Vincent, C., Vincze, A., von der Ohe, M., Von Roenn, N., Vuppalanchi, R., Waters, M., Watt, K., Weltman, M., Wieland, A., Wiener, G., Williams A, A., Williams J, J., Wilson, J., Yataco, M., Yoshida, E., Younes, Z., Yuan, L., Zivony, A., Zogg, D., Zoller, H., Zoulim, F., Zuckerman, E., Zuin, M., Younossi, Zobair M, Ratziu, Vlad, Loomba, Rohit, Rinella, Mary, Anstee, Quentin M, Goodman, Zachary, Bedossa, Pierre, Geier, Andrea, Beckebaum, Susanne, Newsome, Philip N, Sheridan, David, Sheikh, Muhammad Y, Trotter, Jame, Knapple, Whitfield, Lawitz, Eric, Abdelmalek, Manal F, Kowdley, Kris V, Montano-Loza, Aldo J, Boursier, Jerome, Mathurin, Philippe, Bugianesi, Elisabetta, Mazzella, Giuseppe, Olveira, Antonio, Cortez-Pinto, Helena, Graupera, Isabel, Orr, David, Gluud, Lise Lotte, Dufour, Jean-Francoi, Shapiro, David, Campagna, Jason, Zaru, Luna, MacConell, Leigh, Shringarpure, Reshma, Harrison, Stephen, Sanyal, Arun J, Abdelmalek, Manal, Abrams, Gary, Aguilar, Humberto, Ahmed, Aijaz, Aigner, Elmar, Aithal, Guruprasad, Ala, Aftab, Alazawi, William, Albillos, Agustin, Allison, Michael, Al-Shamma, Sfa, Andrade, Raul, Andreone, Pietro, Angelico, Mario, Ankoma-Sey, Victor, Anstee, Quentin, Anty, Rodolphe, Araya, Victor, Arenas Ruiz, Juan Ignacio, Arkkila, Perttu, Arora, Marty, Asselah, Tarik, Au, Jennifer, Ayonrinde, Oyekoya, Bailey, Robert Jame, Balakrishnan, Maya, Bambha, Kiran, Bansal, Meena, Barritt, Sidney, Bate, John, Beato, Jorge, Behari, Jaideep, Bellot, Pablo, Ben Ari, Ziv, Bennett, Michael, Berenguer, Marina, Beretta-Piccoli, Benedetta Terziroli, Berg, Thoma, Bonacini, Maurizio, Bonet, Lucia, Borg, Brian, Bourliere, Marc, Bowman, William, Bradley, David, Brankovic, Marija, Braun, Mariu, Bronowicki, Jean-Pierre, Bruno, Savino, Cai, Cindy, Calleja Panero, José Lui, Carey, Elizabeth, Carmiel, Michal, Carrión, Jose Antonio, Cave, Matthew, Chagas, Cristina, Chami, Tawfik, Chang, Alan, Coates, Allan, Cobbold, Jeremy, Corey, Kathleen, Corless, Lynsey, Crespo, Javier, Cruz Pereira, Oscar, de Ledinghen, Victor, deLemos, Andrew, Diago, Moise, Dufour, Jean-Françoi, Dugalic, Predrag, Dunn, Winston, Elkhashab, Magby, Epstein, Michael, Escudero-Garcia, Maria Desamparado, Etzion, Ohad, Evans, Larry, Falcone, Robert, Fernandez, Conrado, Ferreira, Jose, Fink, Scott, Finnegan, Kevin, Firpi-Morell, Roberto, Floreani, Annarosa, Fontanges, Thierry, Ford, Ryan, Forrest, Ewan, Fowell, Andrew, Fracanzani, Anna Ludovica, Francque, Sven, Freilich, Bradley, Frias, Juan, Fuchs, Michael, Fuentes, Javier, Galambos, Michael, Gallegos, Juan, Geerts, Anja, George, Jacob, Ghali, Maged, Ghalib, Reem, Gholam, Pierre, Gines, Pere, Gitlin, Norman, Goeser, Tobia, Goff, John, Gordon, Stuart, Gordon, Frederic, Goria, Odile, Greer, Shaun, Grigorian, Alla, Gronbaek, Henning, Guillaume, Maeva, Gunaratnam, Naresh, Halegoua-De Marzio, Dina, Hameed, Bilal, Hametner, Stephanie, Hamilton, Jame, Hartleb, Marek, Hassanein, Tarek, Häussinger, Dieter, Hellstern, Paul, Herring, Robert, Heurich, Eva, Hezode, Christophe, Hinrichsen, Holger, Holland Fischer, Peter, Horsmans, Yve, Huang, Jonathan, Jakiche, Antoine, Jeffers, Lennox, Jones, Blake, Jorge, Rosa, Jorquera, Francisco, Kahraman, Alisan, Kaita, Kelly, Karyotakis, Nichola, Kayali, Zeid, Kechagias, Stergio, Kepczyk, Thoma, Khalili, Mandana, Khallafi, Hicham, Kluwe, Johanne, Kohli, Anita, Korenblat, Kevin, Kowdley, Kri, Krag, Aleksander, Krause, Richard, Kremer, Andrea, Krok, Karen, Krstic, Miodrag, Kugelmas, Marcelo, Kumar, Sonal, Labarriere, Damien, Lai, Michelle, Lampertico, Pietro, Lee, Alice, Leroy, Vincent, Lidofsky, Steven, Lim, Tina Huey, Lim, Joseph, Lipkis, Donald, Little, Ester, Lonardo, Amadeo, Long, Michelle, Lurie, Yoav, Macedo, Guilherme, Makara, Mihály, Maliakkal, Benedict, Manns, Michael, Manousou, Pinelopi, Mantry, Parvez, Marchesini, Giulio, Marinho, Carla, Marotta, Paul, Marschall, Hanns-Ulrich, Mayo, Marlyn, McCullen, Mark, McLaughlin, William, Merriman, Raphael, Modi, Apurva, Molina, Esther, Montano-Loza, Aldo, Monteverde, Carlo, Moreea, Sulleman, Moreno, Christophe, Morisco, Filomena, Mubarak, Abdullah, Muellhaupt, Beat, Mukherjee, Sandeep, Müller, Tobia, Nagorni, Aleksandar, Naik, Jahnavi, Neff, Guy, Nevah, Moise, Newsome, Philip, Nguyen-Khac, Eric, Noureddin, Mazen, Oben, Jude, Orlent, Han, Orr, Jame, Ortiz-Lasanta, Grisell, Ozenne, Violaine, Pandya, Prashant, Paredes, Angelo, Park, Jame, Patel, Joykumar, Patel, Keyur, Uta, Merle, Patton, Heather, Peck-Radosavljevic, Marku, Petta, Salvatore, Pianko, Stephen, Piekarska, Anna, Pimstone, Neville, Pockros, Paul, Pol, Stanisla, Porayko, Michael, Poulos, John, Pound, David, Pouzar, Joe, Presa Ramos, Jose, Pyrsopoulos, Nikolao, Rafiq, Nila, Muller, Kate, Ramji, Alnoor, Ravinuthala, Ravi, Reddy, Chakradhar, Reddy K G, Gautham, Reddy K R, K. Rajender, Regenstein, Frederic, Reindollar, Robert, Riera, Andre, Rivera Acosta, Jose, Robaeys, Geert, Roberts, Stuart, Rodriguez-Perez, Federico, Romero-Gomez, Manuel, Rubin, Raymond, Rumi, Mariagrazia, Rushbrook, Simon, Rust, Christian, Ryan, Michael, Safadi, Rifaat, Said, Adnan, Salminen, Kimmo, Samuel, Didier, Santoro, John, Sanyal, Arun, Sarkar, Souvik, Schaeffer, Cynthia, Schattenberg, Jörn, Schiefke, Ingolf, Schiff, Eugene, Schmidt, Wolfgang, Schneider, Jeffrey, Schouten, Jeoffrey, Schultz, Michael, Sebastiani, Giada, Semela, David, Sepe, Thoma, Sheikh, Aasim, Sheikh, Muhammad, Sherman, Kenneth, Shibolet, Oren, Shiffman, Mitchell, Siddique, Asma, Sieberhagen, Cyril, Sigal, Samuel, Sikorska, Katarzyna, Simon, Krzysztof, Sinclair, Marie, Skoien, Richard, Solis, Joel, Sood, Siddharth, Souder, Bob, Spivey, Jame, Stal, Per, Stinton, Laura, Strasser, Simone, Svorcan, Petar, Szabo, Gyongzi, Talal, Andrew, Tam, Edward, Tetri, Brent, Thuluvath, Paul, Tobias, Hillel, Tomasiewicz, Krzysztof, Torres, Dawn, Trauner, Michael, Trautwein, Christian, Tsochatzis, Emanuel, Unitt, Esther, Vargas, Victor, Varkonyi, Istvan, Veitsman, Ella, Vespasiani Gentilucci, Umberto, Victor, David, Vierling, John, Vincent, Catherine, Vincze, Aron, von der Ohe, Manfred, Von Roenn, Natasha, Vuppalanchi, Raj, Waters, Michael, Watt, Kymberly, Weltman, Martin, Wieland, Amanda, Wiener, Gregory, Williams A, Alonzo, Williams J, Jeffrey, Wilson, Jason, Yataco, Maria, Yoshida, Eric, Younes, Ziad, Yuan, Liyun, Zivony, Adam, Zogg, Donald, Zoller, Heinz, Zoulim, Fabien, Zuckerman, Eli, Zuin, Massimo, and REGENERATE Study Investigators

Subjects
Male, Biopsy, Clinical Trial, Phase III, Administration, Oral, 030204 cardiovascular system & hematology, Chronic liver disease, Settore MED/04, Biomarkers/analysis, Gastroenterology, chemistry.chemical_compound, 0302 clinical medicine, Liver Function Tests, Non-alcoholic Fatty Liver Disease, Clinical endpoint, Medicine, 030212 general & internal medicine, 610 Medicine & health, Chenodeoxycholic Acid/administration & dosage, education.field_of_study, Liver Function Test, Research Support, Non-U.S. Gov't, Fatty liver, Obeticholic acid, NASH, OBETICHOLIC ACID, General Medicine, Middle Aged, Multicenter Study, Randomized Controlled Trial, Administration, Female, Biomarkers, Chenodeoxycholic Acid, Double-Blind Method, Humans, Human, Oral, medicine.medical_specialty, Population, Placebo, 03 medical and health sciences, Research Support, N.I.H., Extramural, Internal medicine, Journal Article, education, Intention-to-treat analysis, business.industry, Biomarker, Interim analysis, medicine.disease, Non-alcoholic Fatty Liver Disease/drug therapy, chemistry, Human medicine, business
Abstract

© 2019 Elsevier Ltd. All rights reserved., 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 one accompanying 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 endpoints for 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.

Published
2019
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40. Efficacy of Elbasvir and Grazoprevir in Participants with Hepatitis C Virus Genotype 4 Infection: A Pooled Analysis

Author

Janice Wahl, Tarik Asselah, Hendrik W. Reesink, Bach-Yen Nguyen, Ernest Asante-Appiah, Michael N. Robertson, Peggy Hwang, Victor de Ledinghen, Eliav Barr, Lawrence Serfaty, Rohit Talwani, Paul J. Pockros, Jan Gerstoft, and Other departments

Subjects
Adult, Cyclopropanes, Liver Cirrhosis, Male, medicine.medical_specialty, Elbasvir, Internationality, Genotype, Sustained Virologic Response, Population, Hepacivirus, Antiviral Agents, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Quinoxalines, Internal medicine, Drug Resistance, Viral, Ribavirin, medicine, Clinical endpoint, Humans, 030212 general & internal medicine, NS5A, education, Aged, Benzofurans, Sulfonamides, education.field_of_study, Hepatology, business.industry, Imidazoles, virus diseases, Hepatitis C, Hepatitis C, Chronic, Middle Aged, medicine.disease, Amides, Pooled analysis, Grazoprevir, chemistry, Drug Therapy, Combination, Female, 030211 gastroenterology & hepatology, Carbamates, business
Abstract

Background & aims The aim of this integrated analysis was to assess the efficacy of the once-daily combination of elbasvir 50 mg and grazoprevir 100 mg, with and without ribavirin in HCV genotype 4 (GT4)-infected participants enrolled in the Phase 2/3 clinical programme with elbasvir/grazoprevir. Methods Treatment-naive and treatment-experienced participants 18 years of age or older with chronic HCV GT4 infection and baseline HCV RNA ≥10 000 IU/mL were included in the analysis. The analysis population was the full analysis set (FAS; all participants who received at least 1 dose of study medication) and a total of 155 HCV GT4 participants were evaluated. The primary endpoint was sustained virologic response at week 12 (SVR12; HCV RNA less than the lower limit of quantitation at 12 weeks after the completion of study therapy). Results Overall, among GT4-infected participants treated with 12 or 16 weeks of elbasvir/grazoprevir ± ribavirin, the SVR12 efficacy rates were 96.4% (107/111) in treatment-naive participants and 88.6% (39/44) in treatment-experienced participants. The SVR12 rates were 96.0% (97/101) in treatment-naive participants treated with 12 weeks of elbasvir/grazoprevir and 100% (8/8) in treatment-experienced participants treated with 16 weeks of elbasvir/grazoprevir plus ribavirin. Efficacy was not impacted by GT4 subtype. Conclusions The regimens of 12 weeks of elbasvir/grazoprevir without ribavirin, and 16 weeks of elbasvir/grazoprevir plus ribavirin, were efficacious in HCV GT4-infected treatment-naive and treatment-experienced participants respectively. Baseline NS5A resistance-associated substitutions did not impact the efficacy of elbasvir/grazoprevir in GT4-infected participants.

Published
2018

41. Efficacy of a 12-Week Simeprevir Plus Peginterferon/Ribavirin (PR) Regimen in Treatment-Naïve Patients with Hepatitis C Virus (HCV) Genotype 4 (GT4) Infection and Mild-To-Moderate Fibrosis Displaying Early On-Treatment Virologic Response

Author

Christoph Sarrazin, Oliver Lenz, Faisal M. Sanai, Peter Buggisch, Michael Gschwantler, Christophe Moreno, Catherine Nalpas, Maria Buti, Ceyhun Bicer, I. Lonjon-Domanec, Graham R. Foster, Tarik Asselah, Antonio Craxì, Gino Van Dooren, M. Schlag, Institut Català de la Salut, [Asselah T] Hepatology Department, Beaujon Hospital, University of Paris, Paris, France. [Moreno C] CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium. [Sarrazin C] Johann Wolfgang Goethe University Hospital, Medizinische Klinik 1, Frankfurt am Main, Germany. [Gschwantler M] Department of Internal Medicine IV, Wilhelminenspital, Vienna, Austria. [Foster GR] Queen Mary Hospital, University of London, Barts Health, London, United Kingdom. [Craxí A] Sezione di Gastroenterologia & Epatologia, Di.Bi.M.I.S., University of Palermo, Palermo, Italy. [Buti M] Unitat d'Hepatologia, Vall d’Hebron Hospital, Barcelona, Spain. Ciberehd del Instituto Carlos III, Vall d'Hebron Barcelona Hospital Campus, Asselah T., Moreno C., Sarrazin C., Gschwantler M., Foster G.R., Craxi A., Buggisch P., Sanai F., Bicer C., Lenz O., Van Dooren G., Nalpas C., Lonjon-Domanec I., Schlag M., Buti M., and Grebely, Jason

Subjects
Simeprevir, Male, Psychologie appliquée, Fetge - Malalties, Hepacivirus, Gastroenterology, Polyethylene Glycol, Polyethylene Glycols, 0302 clinical medicine, lcsh:Science, 61 - Medicina, Liver Diseases, Sciences bio-médicales et agricoles, Cirrhosis, Interferon, Liver Fibrosis, 030211 gastroenterology & hepatology, Drug Therapy, Combination, Viral load, Biologie, Human, medicine.medical_specialty, Ciències multidisciplinàries, Genotype, Saudi Arabia, Alpha interferon, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Gastroenterology and Hepatology, Microbiology, Antiviral Agents, 03 medical and health sciences, Humans, Aged, Medicine and health sciences, Hepaciviru, Flaviviruses, Interleukins, lcsh:R, Organisms, Interleukin, medicine.disease, Regimen, Digestive System Diseases::Liver Diseases [DISEASES], chemistry, Immunology, lcsh:Q, Medicaments - Administració, Developmental Biology, RNA viruses, lcsh:Medicine, medicine.disease_cause, Other subheadings::Other subheadings::/drug therapy [Other subheadings], Geographical Locations, chemistry.chemical_compound, Hospital Universitari Vall d’Hebron, 030212 general & internal medicine, Pathology and laboratory medicine, Multidisciplinary, Hepatitis C virus, Hepatitis C, Recombinant Protein, Medical microbiology, Middle Aged, Viral Load, Recombinant Proteins, enfermedades del sistema digestivo::enfermedades hepáticas [ENFERMEDADES], Europe, Research Design, Viruses, Female, Pathogens, Research Article, Adult, Asia, Adolescent, Clinical Research Design, Research and Analysis Methods, Young Adult, Internal medicine, Ribavirin, medicine, ddc:610, Rapid Virologic Response, Antiviral Agent, Biology and life sciences, business.industry, Viral pathogens, Interferon-alpha, Fibrosis, Hepatitis viruses, Microbial pathogens, People and Places, Adverse Events, Interferons, business
Abstract

Background HCV GT4 accounts for up to 20% of HCV infections worldwide. Simeprevir, given for 12 weeks as part of a 24- or 48-week combination regimen with PR is approved for the treatment of chronic HCV GT4 infection. Primary study objectives were assessment of efficacy and safety of simeprevir plus PR in treatment-naïve patients with HCV GT4 treated for 12 weeks. Primary efficacy outcome was sustained virologic response 12 weeks post-treatment (SVR12). Additional objectives included investigation of potential associations of rapid virologic response and baseline factors with SVR12. Methods This multicentre, open-label, single-arm study (NCT01846832) evaluated efficacy and safety of simeprevir plus PR in 67 patients with HCV GT4 infection. Patients were treatment- naïve, aged 18-70 years with METAVIR F0-F2 fibrosis. Patients with early virologic response (HCV RNA, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2017

42. SILEN-C3, a Phase 2 Randomized Trial with Faldaprevir plus Pegylated Interferon α-2a and Ribavirin in Treatment-Naive Hepatitis C Virus Genotype 1-Infected Patients

Author

Thomas Berg, Yakov Datsenko, Tarik Asselah, Peter Ferenci, Stefan Mauss, Marcus Schuchmann, Wulf O. Böcher, Andreas Maieron, Dominique Larrey, Jerry O. Stern, Melek Ozan, Douglas T. Dieterich, Gerhard G. Steinmann, Vlad Ratziu, and Dominique Guyader

Subjects
Male, Aminoisobutyric Acids, Hepacivirus, Viral Nonstructural Proteins, medicine.disease_cause, Gastroenterology, law.invention, Polyethylene Glycols, chemistry.chemical_compound, Randomized controlled trial, law, Pegylated interferon, Pharmacology (medical), Intracellular Signaling Peptides and Proteins, virus diseases, Middle Aged, Hepatitis C, Recombinant Proteins, 3. Good health, Infectious Diseases, Quinolines, RNA, Viral, Drug Therapy, Combination, Female, Oligopeptides, medicine.drug, Adult, medicine.medical_specialty, Adolescent, Genotype, Proline, Hepatitis C virus, Antiviral Agents, Young Adult, Leucine, Internal medicine, Ribavirin, medicine, Humans, Protease inhibitor (pharmacology), Rapid Virologic Response, Aged, Pharmacology, business.industry, Interferon-alpha, Hepatology, Virology, digestive system diseases, Thiazoles, chemistry, Faldaprevir, business, Carrier Proteins
Abstract

Faldaprevir is an investigational hepatitis C virus (HCV) NS3/4A protease inhibitor which, when administered for 24 weeks in combination with pegylated interferon α-2a and ribavirin (PegIFN/RBV) in treatment-naive patients in a prior study (SILEN-C1; M. S. Sulkowski et al., Hepatology 57:2143–2154, 2013, doi:10.1002/hep.26276), achieved sustained virologic response (SVR) rates of 72 to 84%. The current randomized, open-label, parallel-group study compared the efficacy and safety of 12 versus 24 weeks of 120 mg faldaprevir administered once daily, combined with 24 or 48 weeks of PegIFN/RBV, in 160 treatment-naive HCV genotype 1 patients. Patients with maintained rapid virologic response (HCV RNA of IL28B genotype imbalances; IL28B genotype was not tested, as its significance was not known at the time of the study. These results supported phase 3 evaluation. (This study has been registered at ClinicalTrials.gov under registration no. NCT00984620).

Published
2014

44. Accumulation of Intrahepatic TNF-a-Producing NKp44 NK Cells Correlates With Liver Fibrosis and Viral Load in Chronic HCV Infection

Author

Pierre Bedossa, Vivien Béziat, Tarik Asselah, Patrice Debré, Patrick Marcellin, Isabelle Nel, Vincent Vieillard, Olivier Lucar, Caroline Petitdemange, M. Lapalus, Centre d'Immunologie et de Maladies Infectieuses (CIMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'anatomie pathologique [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d’Hépatologie [Hôpital Beaujon], Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], Hôpital Beaujon, Service d'Anatomie et cytologie pathologiques [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and d'Eggis, Gilles

Subjects
Adult, Liver Cirrhosis, Male, 0301 basic medicine, medicine.medical_treatment, Observational Study, Hepacivirus, 03 medical and health sciences, Interleukin 21, Immune system, Non-alcoholic Fatty Liver Disease, medicine, Humans, Aged, Hepatitis, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Natural Cytotoxicity Triggering Receptor 2, Tumor Necrosis Factor-alpha, business.industry, General Medicine, Hepatitis C, Hepatitis C, Chronic, Middle Aged, Viral Load, Flow Cytometry, medicine.disease, 3. Good health, 030104 developmental biology, Cytokine, Liver, Immunology, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Interleukin 12, Female, Tumor necrosis factor alpha, business, Viral hepatitis, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Research Article
Abstract

Supplemental Digital Content is available in the text, In the setting of chronic hepatitis C virus (HCV) infection, changes in natural killer (NK) cells have been shown to reflect activation in response to virus stimulation. The contribution of individual natural cytotoxicity receptors to HCV infection remains to be clarified. NKp44 is the sole specific natural cytotoxicity receptor expressed only on activated NK cells. In this study, peripheral blood and liver NK-cell subsets were purified from 31 patients with chronic C hepatitis or nonalcoholic steatohepatitis, and then characterized by flow cytometry. Their polyfunctional activity was determined by expression of the CD107a degranulation marker, together with intracellular cytokine production. Unlike the patients with nonalcoholic steatohepatitis, patients with chronic HCV infection had a higher frequency of NKp44+ NK cells in the liver than in their peripheral blood (P

Published
2016

45. Natural history and treatment of HCV/HIV coinfection : Is it time to change paradigms?

Author

Tarik Asselah, Andy I. M. Hoepelman, Lauke L. Boeijen, Joop E. Arends, Faydra I. Lieveld, Andrew Ustianowski, Dominique Salmon, Clara T. M. M. de Kanter, and Karel J. van Erpecum

Subjects
Ledipasvir, medicine.medical_specialty, Time Factors, Daclatasvir, Sofosbuvir, Liver fibrosis, HIV Infections, Hepacivirus, Review, Antiviral Agents, Men who have sex with men, chemistry.chemical_compound, medicine, Journal Article, Humans, Intensive care medicine, Didanosine, Hepatology, Coinfection, business.industry, Ribavirin, Stavudine, Disease Management, virus diseases, HIV, Hepatitis C, medicine.disease, digestive system diseases, chemistry, Immunology, Direct-acting antiviral agents, business, Pegylated interferon, medicine.drug
Abstract

Evidence over the past decades have shown that HIV/HCV coinfected patients did not respond as well to HCV therapy as HCV mono-infected patients. However, these paradigms are being recently reassessed with the improvements of care for HIV and HCV patients. This article reviews these original paradigms and how the new data is impacting upon them. Treatment efficacy now appears comparable for HIV/HCV coinfected and HCV mono-infected patients, while liver fibrosis progression is increasingly similar in optimally managed patients. Additional importance of therapy is directed to drug-drug interactions and the impact of HCV reinfection, as well as the possibility of transmitted drug resistance.

Published
2015

46. P16 SOF/VEL/VOX for 8 or 12 weeks results in high SVR12 rates: an integrated analysis of the POLARIS-1, POLARIS-2, POLARIS-3 AND POLARIS-4 studies

Author

Stefan Zeuzem, Kris V. Kowdley, Tarik Asselah, Stuart K. Roberts, Michael Manns, Steven L. Flamm, Bernard Willems, Marc Bourlière, Luisa M. Stamm, Ira M. Jacobson, Edward Gane, Stuart C. Gordon, K. Rajender Reddy, Norbert Bräu, Curtis Cooper, Alexander J. Thompson, Graham R. Foster, Eric Lawitz, Lingling Han, Diana M. Brainard, Peter Ruane, and Robert H. Hyland

Subjects
Infectious Diseases, Polaris, Epidemiology, Virology, Immunology, Public Health, Environmental and Occupational Health, Environmental science, Astronomy, Public aspects of medicine, RA1-1270, Microbiology, QR1-502
Published
2017

47. Sustained virological response is associated with clearance of hepatitis C virus RNA and a decrease in hepatitis C virus antibody

Author

Sarah, Maylin, Michelle, Martinot-Peignoux, Marie-Pierre, Ripault, Rami, Moucari, Ana Carolina, Cardoso, Nathalie, Boyer, Nathalie, Giuily, Corinne, Castelnau, Michelle, Pouteau, Tarik, Asselah, Marie Hélène, Nicolas-Chanoine, and Patrick, Marcellin

Subjects
Adult, Male, Time Factors, Hepacivirus, residual infection, Interferon alpha-2, Antiviral Agents, Young Adult, transcription-mediated amplification (TMA), Clinical Studies, HCV antibody, Humans, pegylated interferon, Aged, Remission Induction, virus diseases, Interferon-alpha, Alanine Transaminase, Hepatitis C Antibodies, Middle Aged, Hepatitis C, Chronic, Viral Load, RIBA-HCV, digestive system diseases, Recombinant Proteins, Treatment Outcome, RNA, Viral, Female, Follow-Up Studies
Abstract

Background/Aim Viral eradication in chronic hepatitis C patients with sustained virological response (SVR) after interferon (IFN) therapy remains controversial. Methods During a long-term follow-up study, 157 patients with SVR to IFN-α-2b-based therapy were investigated with a transcription-mediated amplification (TMA) assay in serum. The hepatitis C virus (HCV) antibody was assessed by measuring the optical density (OD) (Axsym HCV v3.0) and the semiquantitative titres (RIBA HCV v3.0) of the HCV antibodies directed against the core, NS3, NS4 and NS5 proteins. A control group included 23 untreated patients with persistently normal serum alanine aminotransferase and detectable serum HCV-RNA. Results The median duration of follow-up was 4.0 (0–10) years. Serum HCV-RNA remained undetectable in all patients. The mean HCV antibody OD were 93 ± 19 and 45 ± 21 before therapy and in the last available serum sample respectively (P=0.001). There was a marked decrease in the HCV antibodies directed against the NS3, NS4 and NS5 proteins (P=0.001), while the core protein titre remained strongly positive. The 23 control patients were followed for a median of 5 (2–14) years. The mean HCV antibody OD were 65 ± 14 and 64 ± 19 in the first and the last measurements, respectively (NS), and HCV antibody titres for structural and non-structural proteins remained unchanged. Conclusion This long-term study evaluating 157 patients demonstrated that SVR assessed by TMA is durable, and HCV antibodies were markedly decreased (mainly those directed against the non-structural proteins), emphasizing an absence of ongoing infection. These results strongly suggest that HCV infection cured in patients who achieve an SVR.

Published
2009

48. STARTVerso1: A Randomized Trial of Faldaprevir Plus Pegylated Interferon/Ribavirin for Chronic HCV Genotype-1 Infection

Author

Denis Ouzan, Shuhei Nishiguchi, Anne-Marie Quinson, George Kukolj, Jerry O. Stern, Christophe Moreno, Joseph Scherer, M. V. Maevskaya, L. Morano, Filipe Calinas, Peter Ferenci, Masao Omata, Kosh Agarwal, Graham R. Foster, Yakov Datsenko, Jean-François Dufour, Marc Bourlière, Elmar Zehnter, Stefan Zeuzem, Javier Crespo, Miguel Garcia, Daniel M. Forton, Tarik Asselah, Marcus Schuchmann, and Christoph Sarrazin

Subjects
Male, Aminoisobutyric Acids, Recombinant Proteins/administration & dosage, Ribavirin/adverse effects, Hepacivirus, Polyethylene Glycols/adverse effects, Pharmacology, medicine.disease_cause, Gastroenterology, Polyethylene Glycols, chemistry.chemical_compound, Pegylated interferon, Thiazoles/administration & dosage, Interferon-alpha/adverse effects, virus diseases, Middle Aged, Antiviral Agents/adverse effects, Recombinant Proteins, Tolerability, Quinolines, RNA, Viral, Drug Therapy, Combination, Female, Oligopeptides, Antiviral Agents/administration & dosage, Hepacivirus/classification, medicine.drug, Adult, medicine.medical_specialty, Proline, Genotype, Hepatitis C virus, Interferon-alpha/administration & dosage, Alpha interferon, Hepacivirus/genetics, 610 Medicine & health, Placebo, Antiviral Agents, Oligopeptides/administration & dosage, Hepatitis C, Chronic/drug therapy, Double-Blind Method, Leucine, Internal medicine, Hepatitis C, Chronic/virology, Ribavirin, medicine, Recombinant Proteins/adverse effects, Humans, RNA, Viral/blood, Polyethylene Glycols/administration & dosage, Intention-to-treat analysis, Hepatology, business.industry, Hepacivirus/drug effects, Interferon-alpha, Hepatitis C, Chronic, CHLC GAS, Thiazoles, Thiazoles/adverse effects, chemistry, Faldaprevir, business, Ribavirin/administration & dosage, Oligopeptides/adverse effects
Abstract

BACKGROUND & AIMS The efficacy and tolerability of faldaprevir, a potent hepatitis C virus (HCV) NS3/4A protease inhibitor, plus peginterferon and ribavirin was assessed in a double-blind, placebo-controlled phase 3 study of treatment-naïve patients with HCV genotype-1 infection. METHODS Patients were randomly assigned (1:2:2) to peginterferon/ribavirin plus: placebo (arm 1, n=132) for 24 weeks; faldaprevir (120 mg, once daily) for 12 or 24 weeks (arm 2, n=259); or faldaprevir (240 mg, once daily) for 12 weeks (arm 3, n=261). In arms 2 and 3, patients with early treatment success (HCV RNA

Published
2015

49. Efficacy and Safety of Faldaprevir, Deleobuvir, and Ribavirin in Treatment-Naive Patients with Chronic Hepatitis C Virus Infection and Advanced Liver Fibrosis or Cirrhosis

Author

John P. Sabo, Ansgar W. Lohse, Maria Buti, Stefan Zeuzem, Stuart K. Roberts, Beat Müllhaupt, Tarik Asselah, John-Paul Gallivan, Marcus Schuchmann, Jean-Pierre Bronowicki, Florian Voss, Felix Stickel, Edward Gane, Wulf O. Böcher, Federico J. Mensa, Marc Bourlière, Michael Manns, Peter W Angus, Jerry O. Stern, Vicente Soriano, Johann Wolfgang Goethe University Medical Center, Department of Infectious Diseases, Hospital Carlos III, Department of hepatology, Hôpital Beaujon, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Auckland Clinical Studies (ACS), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Austin Health, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), University of Bern, University hospital of Zurich [Zurich], Alfred Hospital, University Clinics Mainz, Hannover Medical School [Hannover] (MHH), Service d'hépato-gastro-entérologie, Assistance Publique - Hôpitaux de Marseille (APHM), Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Liver Unit, Clínica Universitaria, CIBER-EHD, Universitario Valle de Hebron, Boehringer Ingelheim Pharmaceuticals, Boehringer Ingelheim Pharma GmbH & Co, Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Vall d'Hebron University Hospital [Barcelona], University of Zurich, and Zeuzem, Stefan

Subjects
Adult, Liver Cirrhosis, Male, medicine.medical_specialty, Aminoisobutyric Acids, Cirrhosis, Proline, [SDV]Life Sciences [q-bio], 610 Medicine & health, Gastroenterology, Antiviral Agents, chemistry.chemical_compound, Young Adult, Leucine, Fibrosis, Internal medicine, Ribavirin, medicine, 2736 Pharmacology (medical), Humans, Pharmacology (medical), Aged, Pharmacology, Aged, 80 and over, business.industry, Deleobuvir, 2725 Infectious Diseases, Hepatitis C, Hepatitis C, Chronic, Middle Aged, medicine.disease, 3. Good health, Regimen, Thiazoles, 10219 Clinic for Gastroenterology and Hepatology, 3004 Pharmacology, Infectious Diseases, chemistry, Acrylates, Faldaprevir, Quinolines, Benzimidazoles, Female, business, Hepatic fibrosis, Oligopeptides
Abstract

Patients with advanced hepatic fibrosis or cirrhosis with chronic hepatitis C virus (HCV) infection represent an unmet need. The HCV NS3/4A inhibitor, faldaprevir, was evaluated in combination with the nonnucleoside NS5B inhibitor, deleobuvir, with or without ribavirin in treatment-naive patients with HCV genotype 1 infection in the SOUND-C2 study. Here, the efficacy and safety of this interferon-free regimen in a subset of patients with advanced liver fibrosis, including those with compensated cirrhosis, were assessed. Patients (n= 362) were randomized to once-daily faldaprevir with either twice-daily (BID) or three-times-daily (TID) deleobuvir for 16 (TID16W), 28 (TID28W and BID28W), or 40 (TID40W) weeks with or without ribavirin (TID28W-NR). Patients were classified according to fibrosis stage (F0 to F2 versus F3 to F4) and the presence of cirrhosis (yes/no). In total, 85 (24%) patients had advanced fibrosis/cirrhosis (F3 to F4) and 33 (9%) had cirrhosis. Within each treatment arm, differences in rates of sustained virologic response 12 weeks after completion of treatment (SVR12) between patients with mild to moderate fibrosis (F0 to F2) versus F3 to F4 did not show a consistent pattern and were not statistically significant (63% versus 47% for TID16W, 53% versus 76% for TID28W, 48% versus 67% for TID40W, 70% versus 67% for BID28W, and 40% versus 36% for TID28W-NR, respectively;P> 0.05 for each arm). The most frequent adverse events in patients with/without cirrhosis were gastrointestinal and skin events, which were mostly mild or moderate in intensity. The degree of liver fibrosis did not appear to affect the probability of achieving SVR12 following treatment with the interferon-free regimen of faldaprevir, deleobuvir, and ribavirin. (This study has been registered at ClinicalTrials.gov under registration no. NCT01132313.)

Published
2015

50. ITPA Genotypes Predict Anemia but Do Not Affect Virological Response with Interferon-Free Faldaprevir, Deleobuvir, and Ribavirin for HCV Infection

Author

Federico J. Mensa, Tarik Asselah, Marc Bourlière, Jerry O. Stern, Beat Müllhaupt, Edward Gane, Wulf O. Böcher, Vicente Soriano, John-Paul Gallivan, Jean-Pierre Bronowicki, Patrick Baum, Marcus Schuchmann, Florian Voss, Stuart K. Roberts, Maria Buti, Stefan Zeuzem, Ansgar W. Lohse, University of Zurich, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d’Hépatologie [Hôpital Beaujon], Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), J.-W. Goethe-University Hospital, Department of Infectious Diseases, Hospital Carlos III, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Division of Gastroenterology and Hepatology [Stadtspital Triemli Zurich], Stadtspital Triemli Zürich, University Hospital Johannes-Gutenberg University Mainz, Service d'Hépato-Gastroentérologie, Hôpital St Joseph, Hospital General, Vall d'Hebron University Hospital [Barcelona], Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Liver Unit, Clínica Universitaria, CIBER-EHD, Alfred Hospital, Auckland Clinical Studies (ACS), Boehringer Ingelheim Pharma GmbH & Co, and UL, NGERE

Subjects
Male, Aminoisobutyric Acids, viruses, [SDV]Life Sciences [q-bio], lcsh:Medicine, Hepacivirus, medicine.disease_cause, Gastroenterology, chemistry.chemical_compound, 0302 clinical medicine, Genotype, 030212 general & internal medicine, Pyrophosphatases, lcsh:Science, Multidisciplinary, Hepatitis C virus, virus diseases, Anemia, Middle Aged, Hepatitis C, 3. Good health, [SDV] Life Sciences [q-bio], 10219 Clinic for Gastroenterology and Hepatology, Acrylates, Genetic interference, Quinolines, 030211 gastroenterology & hepatology, Female, ITPA, Oligopeptides, Research Article, medicine.medical_specialty, Proline, 610 Medicine & health, 1100 General Agricultural and Biological Sciences, Real-Time Polymerase Chain Reaction, Antiviral Agents, Polymorphism, Single Nucleotide, 03 medical and health sciences, Leucine, 1300 General Biochemistry, Genetics and Molecular Biology, Internal medicine, Ribavirin, medicine, Humans, ddc:610, Hemoglobin, Variant genotypes, 1000 Multidisciplinary, business.industry, lcsh:R, Deleobuvir, Protease inhibitor therapy, medicine.disease, Inosine, digestive system diseases, Thiazoles, chemistry, Multivariate analysis, Faldaprevir, Immunology, Benzimidazoles, lcsh:Q, Interferons, business
Abstract

BACKGROUND & AIM:Whether inosine triphosphatase (ITPA) gene polymorphisms predict anemia during interferon-free therapy in chronic hepatitis C virus (HCV)-infected patients is unknown. We examined the relationship between two ITPA polymorphisms, anemia, and sustained virological response 12 weeks post-treatment (SVR12) in patients receiving the NS3/4A protease inhibitor faldaprevir, the non-nucleoside polymerase inhibitor deleobuvir, and ribavirin. METHODS:HCV genotype 1-infected, treatment-naïve patients (N = 362) were randomized and treated in one of five treatment arms with faldaprevir and deleobuvir with or without ribavirin. Two ITPA polymorphisms (rs1127354 and rs6051702) were genotyped and defined as ITPA-deficient (rs1127354 AA or AC; rs6051702 CC or CA) or ITPA-non-deficient (rs1127354 CC; rs6051702 AA) according to their association with ITPA deficiency. Baseline and on-treatment variables associated with anemia and SVR12 were identified using logistic regression. RESULTS:In the pooled ribavirin-containing arms, 10.1% (32/316) of patients experienced on-treatment hemoglobin

Published
2015

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