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1
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Zarębska-Michaluk D, Flisiak R, Janczewska E, Berak H, Mazur W, Janocha-Litwin J, Krygier R, Dobracka B, Jaroszewicz J, Parfieniuk-Kowerda A, Dobrowolska K, Rzymski P. Does a detectable HCV RNA at the end of DAA therapy herald treatment failure? Antiviral Res 2023; 220:105742. [PMID: 37944825 DOI: 10.1016/j.antiviral.2023.105742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 10/23/2023] [Accepted: 10/29/2023] [Indexed: 11/12/2023]
Abstract
BACKGROUND & AIMS The study aimed to assess the phenomenon of achieving sustained virologic response (SVR) in patients with detectable ribonucleic acid (RNA) of hepatitis C virus (HCV) at the end of treatment (ET) with direct-acting antivirals (DAA), find how this is affected by the type of regimen, and how patients experiencing this differed from non-responders with detectable HCV RNA at the ET. METHODS The study included all consecutive patients with detectable HCV RNA at the ET selected from the EpiTer-2 database, a retrospective national multicentre project evaluating antiviral treatment in HCV-infected patients in 2015-2023. RESULTS Of the 16106 patients treated with IFN-free regimens with available HCV RNA assessment at the ET and at follow-up 12 weeks after treatment completion (FU), 1253 (7.8%) had detectable HCV RNA at the ET, and 1120 of them (89%) finally achieved SVR. This phenomenon was significantly more frequent in pangenotypic regimens, 10.3% vs. 4.7% in genotype-specific options (p < 0.001), and the highest proportion was documented for glecaprevir/pibrentasvir (13.7%), and velpatasvir/sofosbuvir ± ribavirin (6.9%). Patients ET + FU- treated with these two pangenotypic regimens (n = 668) had less advanced liver disease, were less frequently infected with genotype (GT) 3, and were significantly more likely to be treatment-naïve than 61 non-responders. CONCLUSIONS We documented 7.8% rate of patients with detectable HCV RNA at the ET, of whom 89% subsequently achieved SVR, significantly more frequently in the population treated with pangenotypic regimens. Less severe liver disease, more often GT3 infection, and a higher percentage of treatment-naive patients distinguished this group from non-responders.
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Affiliation(s)
- Dorota Zarębska-Michaluk
- Department of Infectious Diseases and Allergology, Jan Kochanowski University, 25-317, Kielce, Poland.
| | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, 15-540, Białystok, Poland
| | - Ewa Janczewska
- Department of Basic Medical Sciences, School of Public Health in Bytom, Medical University of Silesia, 40-055, Katowice, Poland
| | - Hanna Berak
- Outpatient Clinic, Hospital for Infectious Diseases in Warsaw, 01-201, Warsaw, Poland
| | - Włodzimierz Mazur
- Clinical Department of Infectious Diseases in Chorzów, Medical University of Silesia, 40-055, Katowice, Poland
| | - Justyna Janocha-Litwin
- Department of Infectious Diseases and Hepatology, Wrocław Medical University, 50-367, Wrocław, Poland
| | - Rafał Krygier
- Infectious Diseases and Hepatology Outpatient Clinic NZOZ "Gemini", 62-571, Żychlin, Poland
| | | | - Jerzy Jaroszewicz
- Department of Infectious Diseases and Hepatology, Medical University of Silesia, 40-055, Katowice, Poland
| | - Anna Parfieniuk-Kowerda
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, 15-540, Białystok, Poland
| | | | - Piotr Rzymski
- Department of Environmental Medicine, Poznań University of Medical Sciences, 60-806, Poznań, Poland
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2
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Ji Q, Chu X, Zhou Y, Liu X, Zhao W, Ye W. Safety and efficacy of grazoprevir/elbasvir in the treatment of acute hepatitis C in hemodialysis patients. J Med Virol 2022; 94:675-682. [PMID: 34599755 PMCID: PMC9298284 DOI: 10.1002/jmv.27374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 09/07/2021] [Accepted: 09/30/2021] [Indexed: 11/18/2022]
Abstract
Treatment of hepatitis C virus (HCV) infection with direct-acting antiviral agents (DAAs) in hemodialysis patients requires extensive consideration. At present, studies regarding DAAs for acute HCV infection in such patients are limited. The present study aims to evaluate the efficacy and safety of grazoprevir (GZR) plus elbasvir (EBR) treatment in acute hepatitis C (AHC) patients undergoing hemodialysis. Patients undergoing hemodialysis who had a nosocomial acute HCV infection were enrolled. All patients received GZR 100 mg/EBR 50 mg once daily for 12 weeks and were followed up for 12 weeks. Serum alanine transaminase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), and HCV RNA levels were monitored during treatment and follow-up periods. Sustained virologic response at 12 weeks after treatment cessation and treatment-emergent adverse events (AEs) were assessed. A total of 68 AHC patients were enrolled. All patients were infected with HCV genotype 1b and achieved SVR12. Decreasing ALT, AST, and TBIL were observed over time in the first 4 weeks and became steady thereafter. Forty-eight (70.59%) patients reported at least one AEs. The most common AEs were fatigue, headache, and nausea. Two AHC patients discontinued treatment due to serious but drug-unrelated AEs. In conclusion, GZR/EBR has a high efficacy and safety profile in hemodialysis-dependent patients with genotype 1b AHC.
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Affiliation(s)
- Qinghua Ji
- Department of Infectious Disease, School of MedicineSoutheast UniversityNanjingJiangsuChina
| | - Xudong Chu
- Department of Infectious DiseasesThe Affiliated Dongtai Hospital of Nantong UniversityDongtaiJiangsuChina
| | - Yugui Zhou
- Department of Clinical LaboratoryThe Affiliated Dongtai Hospital of Nantong UniversityDongtaiJiangsuChina
| | - Xuan Liu
- Department of Clinical LaboratoryThe Second Hospital of NanjingNanjingJiangsuChina
| | - Wei Zhao
- Department of Infectious Disease, School of MedicineSoutheast UniversityNanjingJiangsuChina
| | - Wei Ye
- Department of Liver DiseaseThe Second Hospital of Nanjing, Southeast UniversityNanjingJiangsuChina
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3
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Merino GA, Raad J, Bugnon LA, Yones C, Kamenetzky L, Claus J, Ariel F, Milone DH, Stegmayer G. Novel SARS-CoV-2 encoded small RNAs in the passage to humans. Bioinformatics 2021; 36:5571-5581. [PMID: 33244583 PMCID: PMC7717134 DOI: 10.1093/bioinformatics/btaa1002] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 10/15/2020] [Accepted: 11/18/2020] [Indexed: 12/14/2022] Open
Abstract
Motivation The Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) has recently emerged as the responsible for the pandemic outbreak of the coronavirus disease (COVID-19). This virus is closely related to coronaviruses infecting bats and Malayan pangolins, species suspected to be an intermediate host in the passage to humans. Several genomic mutations affecting viral proteins have been identified, contributing to the understanding of the recent animal-to-human transmission. However, the capacity of SARS-CoV-2 to encode functional putative microRNAs (miRNAs) remains largely unexplored. Results We have used deep learning to discover 12 candidate stem-loop structures hidden in the viral protein-coding genome. Among the precursors, the expression of eight mature miRNAs-like sequences was confirmed in small RNA-seq data from SARS-CoV-2 infected human cells. Predicted miRNAs are likely to target a subset of human genes of which 109 are transcriptionally deregulated upon infection. Remarkably, 28 of those genes potentially targeted by SARS-CoV-2 miRNAs are down-regulated in infected human cells. Interestingly, most of them have been related to respiratory diseases and viral infection, including several afflictions previously associated with SARS-CoV-1 and SARS-CoV-2. The comparison of SARS-CoV-2 pre-miRNA sequences with those from bat and pangolin coronaviruses suggests that single nucleotide mutations could have helped its progenitors jumping inter-species boundaries, allowing the gain of novel mature miRNAs targeting human mRNAs. Our results suggest that the recent acquisition of novel miRNAs-like sequences in the SARS-CoV-2 genome may have contributed to modulate the transcriptional reprogramming of the new host upon infection.
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Affiliation(s)
- Gabriela A Merino
- Research Institute for Signals, Systems and Computational Intelligence (sinc(i)), FICH-UNL, CONICET, Ciudad Universitaria UNL, Santa Fe 3000, Argentina.,Bioengineering and Bioinformatics Research and Development Institute (IBB), FI-UNER, CONICET, Entre Ríos 3100, Argentina.,European Molecular Biology Laboratory, European Bioinformatics Institute, Cambridgeshire CB101SD, UK
| | - Jonathan Raad
- Research Institute for Signals, Systems and Computational Intelligence (sinc(i)), FICH-UNL, CONICET, Ciudad Universitaria UNL, Santa Fe 3000, Argentina
| | - Leandro A Bugnon
- Research Institute for Signals, Systems and Computational Intelligence (sinc(i)), FICH-UNL, CONICET, Ciudad Universitaria UNL, Santa Fe 3000, Argentina
| | - Cristian Yones
- Research Institute for Signals, Systems and Computational Intelligence (sinc(i)), FICH-UNL, CONICET, Ciudad Universitaria UNL, Santa Fe 3000, Argentina
| | - Laura Kamenetzky
- Instituto de Investigaciones en Microbiología y Parasitología Médica (IMPaM), Facultad de Medicina, UBA-CONICET, Ciudad Autónoma de Buenos Aires 1121, Argentina.,Laboratorio de Genómica y Bioinformática de Patógenos, iB3, Instituto de Biociencias, Biotecnología y Biología traslacional, Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires 1121, Argentina
| | - Juan Claus
- Laboratorio de Virología, FBCB, Ciudad Universitaria UNL, Santa Fe 3000, Argentina
| | - Federico Ariel
- Instituto de Agrobiotecnología del Litoral (IAL), CONICET, FBCB, Universidad Nacional del Litoral, Santa Fe 3000, Argentina
| | - Diego H Milone
- Research Institute for Signals, Systems and Computational Intelligence (sinc(i)), FICH-UNL, CONICET, Ciudad Universitaria UNL, Santa Fe 3000, Argentina
| | - Georgina Stegmayer
- Research Institute for Signals, Systems and Computational Intelligence (sinc(i)), FICH-UNL, CONICET, Ciudad Universitaria UNL, Santa Fe 3000, Argentina
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4
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Balagopal A, Smeaton LM, Quinn J, Venuto CS, Morse GD, Vu V, Alston-Smith B, Cohen DE, Santana-Bagur JL, Anthony DD, Sulkowski MS, Wyles DL, Talal AH. Intrahepatic Viral Kinetics During Direct-Acting Antivirals for Hepatitis C in Human Immunodeficiency Virus Coinfection: The AIDS Clinical Trials Group A5335S Substudy. J Infect Dis 2021; 222:601-610. [PMID: 32201883 DOI: 10.1093/infdis/jiaa126] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 03/20/2020] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Direct-acting antivirals (DAAs) targeting hepatitis C virus (HCV) have revolutionized outcomes in human immunodeficiency virus (HIV) coinfection. METHODS We examined early events in liver and plasma through A5335S, a substudy of trial A5329 (paritaprevir/ritonavir, ombitasvir, dasabuvir, with ribavirin) that enrolled chronic genotype 1a HCV-infected persons coinfected with suppressed HIV: 5 of 6 treatment-naive enrollees completed A5335S. RESULTS Mean baseline plasma HCV ribonucleic acid (RNA) = 6.7 log10 IU/mL and changed by -4.1 log10 IU/mL by Day 7. In liver, laser capture microdissection was used to quantify HCV. At liver biopsy 1, mean %HCV-infected cells = 25.2% (95% confidence interval [CI], 7.4%-42.9%), correlating with plasma HCV RNA (Spearman rank correlation r = 0.9); at biopsy 2 (Day 7 in 4 of 5 participants), mean %HCV-infected cells = 1.0% (95% CI, 0.2%-1.7%) (P < .05 for change), and DAAs were detectable in liver. Plasma C-X-C motif chemokine 10 (CXCL10) concentrations changed by mean = -160 pg/mL per day at 24 hours, but no further after Day 4. CONCLUSIONS We conclude that HCV infection is rapidly cleared from liver with DAA leaving <2% HCV-infected hepatocytes at Day 7. We extrapolate that HCV eradication could occur in these participants by 63 days, although immune activation might persist. Single-cell longitudinal estimates of HCV clearance from liver have never been reported previously and could be applied to estimating the minimum treatment duration required for HCV infection.
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Affiliation(s)
- Ashwin Balagopal
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Laura M Smeaton
- Harvard T.H. Chan School of Public Health, Boston, Masachussetts, USA
| | - Jeffrey Quinn
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Charles S Venuto
- Center for Health + Technology, University of Rochester, Rochester, New York, USA
| | - Gene D Morse
- Center for Integrated Global Biomedical Sciences, University at Buffalo, Buffalo, New York, USA
| | - Vincent Vu
- Harvard T.H. Chan School of Public Health, Boston, Masachussetts, USA
| | | | | | | | | | - Mark S Sulkowski
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - David L Wyles
- University of Colorado School of Medicine, Denver, Colorado, USA
| | - Andrew H Talal
- Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, USA
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5
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Effect of Low Positive End of Treatment Viral Load with Direct-Acting Antiviral Therapy on Sustained Virologic Response. Can J Gastroenterol Hepatol 2020; 2020:8815829. [PMID: 32802821 PMCID: PMC7403896 DOI: 10.1155/2020/8815829] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 06/23/2020] [Accepted: 07/01/2020] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Direct-acting antivirals (DAAs) are highly effective treatments against hepatitis C virus (HCV), with sustained virologic response (SVR) rates of 93-100% against all genotypes. In most patients, viral load (VL) becomes undetectable four weeks into treatment, but rarely a low positive VL may be observed at the end of treatment (EOT). This study was conducted to determine the effect of low positive EOT VLs with DAA therapies on SVR at 12 and 24 weeks. METHODS A retrospective chart review was conducted from January 2014 to December 2018 on 1256 HCV patients of all genotypes (1-6) who had received DAA therapy at two large hepatology referral centers. Baseline demographic data, along with VL at week four, EOT, and SVR12/24 time points were collected for patients that had positive EOT VL. Treatment outcome for any patient with positive EOT VL was noted. RESULTS Eight out of 1256 patients treated with varying DAA therapies were observed to have low positive EOT VLs ranging from <15 to 235 IU/mL. One patient had a negative EOT VL, but 23 IU/mL at week four after EOT. All eight patients who had low positive EOT VLs and one patient who had a low positive VL at four weeks after EOT achieved SVR at weeks 12 and 24. One of the eight patients had cirrhosis. The majority of patients were genotype 1a. CONCLUSION In the DAA treatment era, low levels of detectable HCV RNA at EOT does not predict treatment failure.
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6
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Paolucci S, Novazzi F, Piralla A, Maserati R, Gulminetti R, Novati S, Barbarini G, Sacchi P, Fratini A, Bellotti L, Baldanti F. Viral dynamics among HCV infected patients with different genotypes treated with genotypic specific or pan-genotypic direct-acting antiviral agent combinations. Infect Drug Resist 2019; 12:1975-1984. [PMID: 31372005 PMCID: PMC6627173 DOI: 10.2147/idr.s205282] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 03/25/2019] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND New hepatitis C virus (HCV) therapies have improved efficacy, allowed pangenotypic applications, increased barriers to drug resistance and shortened therapy duration. METHODS Patients infected with different HCV genotypes were divided into two groups: group 1 included 169 patients receiving genotypic specific regimens (GSR), while group 2 included 186 patients receiving pan-genotypic regimens (PGR). Patient's HCV RNA was quantified and sequenced. RESULTS Comparable sustained viral response (SVR) rates were observed in both GSR and PGR treated patients. Nevertheless, even if not significant, a greater proportion of non-detectable levels (NDL) of HCV RNA was observed in patients treated with PGR as compared with GSR. Overall, among patients in the GSR and PGR groups with residual viremia, 124/169 (73.4%) and 125/186 (67.2%) at four weeks, and 66/169 (39.1%) and 58/186 (31.2%) at eight weeks, achieved SVR. No difference was observed in the clinical outcome comparing patients in the GSR and PGR groups according to genotype. While, comparing patients between the two groups, the proportion of patients with NDL HCV RNA at four and eight weeks was higher in patients infected with genotype 1b treated with PGR (p=0.0015). A significantly higher number of patients infected with 1b had RASs at baseline (p=0.0001). In addition, the proportion of patients with treatment failure was higher in patients with RASs at baseline compared with those without (p=0.012). Overall, 2.5% patients failed to achieve SVR after DAA treatment. CONCLUSION A sharp HCV RNA decrease was observed in patients treated with both GSR and PGR. However, even if comparable, a slightly greater number of patients treated with PGR achieved NDL HCV RNA as compared with GSR. A significant difference was observed in patients with baseline RASs, both in relation to treatment failure and genotype. In conclusion, the use of new DAA combinations helps patients achieve a more rapid virologic response.
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Affiliation(s)
- Stefania Paolucci
- Molecular Virology Unit, Microbiology and Virology Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico, San Matteo, Pavia, Italy
| | - Federica Novazzi
- Molecular Virology Unit, Microbiology and Virology Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico, San Matteo, Pavia, Italy
| | - Antonio Piralla
- Molecular Virology Unit, Microbiology and Virology Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico, San Matteo, Pavia, Italy
| | - Renato Maserati
- Institute of Infectious Diseases, University of Pavia, Pavia, Italy
| | | | - Stefano Novati
- Institute of Infectious Diseases, University of Pavia, Pavia, Italy
| | - Giorgio Barbarini
- Division of Infectious and Tropical Diseases, Fondazione IRCCS Policlinico, San Matteo, Pavia, Italy
| | - Paolo Sacchi
- Division of Infectious and Tropical Diseases, Fondazione IRCCS Policlinico, San Matteo, Pavia, Italy
| | - Alice Fratini
- Molecular Virology Unit, Microbiology and Virology Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico, San Matteo, Pavia, Italy
| | - Laura Bellotti
- Molecular Virology Unit, Microbiology and Virology Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico, San Matteo, Pavia, Italy
| | - Fausto Baldanti
- Molecular Virology Unit, Microbiology and Virology Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico, San Matteo, Pavia, Italy
- Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
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7
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Raja R, Baral S, Dixit NM. Interferon at the cellular, individual, and population level in hepatitis C virus infection: Its role in the interferon-free treatment era. Immunol Rev 2019; 285:55-71. [PMID: 30129199 DOI: 10.1111/imr.12689] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The advent of powerful direct-acting antiviral agents (DAAs) has revolutionized the treatment of hepatitis C. DAAs cure nearly all patients with short duration, oral treatments. Significant efforts are now underway to optimize DAA-based treatments. We discuss the potential role of interferon in this optimization. Clinical studies present compelling evidence that DAAs perform better in treatment-naive individuals than in individuals who previously failed treatment with interferon, a surprising correlation because interferon and DAAs are thought to act independently. Recent mathematical models explore a mechanistic hypothesis underlying this correlation. The hypothesis invokes the action of interferon at the cellular, individual, and population levels. Strong interferon responses prevent the productive infection of cells, reduce viral replication, and impede the development of resistance to DAAs in infected individuals and improve cure rates elicited by DAAs in treated populations. The models develop descriptions of these processes, integrate them into a comprehensive framework, and capture clinical data quantitatively, providing a successful test of the hypothesis. Individuals with strong endogenous interferon responses thus present a promising subpopulation for reducing DAA treatment durations. This review discusses the conceptual advances made by the models, highlights the new insights they unravel, and examines their applicability to optimize DAA-based treatments.
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Affiliation(s)
- Rubesh Raja
- Department of Chemical Engineering, Indian Institute of Science, Bangalore, India
| | - Subhasish Baral
- Department of Chemical Engineering, Indian Institute of Science, Bangalore, India
| | - Narendra M Dixit
- Department of Chemical Engineering, Indian Institute of Science, Bangalore, India.,Centre for Biosystems Science and Engineering, Indian Institute of Science, Bangalore, India
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8
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Loggi E, Vukotic R, Conti F, Gitto S, Andreone P. Gold Standard Assays for the Monitoring of Patients With Chronic Hepatitis C. Future Virol 2018; 13:529-537. [DOI: 10.2217/fvl-2018-0032] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2018] [Accepted: 05/17/2018] [Indexed: 01/16/2023]
Affiliation(s)
- Elisabetta Loggi
- Dipartimento di Scienze Mediche e Chirurgiche Centro di Ricerca per lo Studio delle Epatiti Università degli Studi di Bologna
Bologna
Italy
- Current address: UOC Patologia Clinica ASUR Area Vasta 4
Fermo (FM)
Italy
| | - Ranka Vukotic
- Dipartimento di Scienze Mediche e Chirurgiche Centro di Ricerca per lo Studio delle Epatiti Università degli Studi di Bologna
Bologna
Italy
| | - Fabio Conti
- Dipartimento di Scienze Mediche e Chirurgiche Centro di Ricerca per lo Studio delle Epatiti Università degli Studi di Bologna
Bologna
Italy
| | - Stefano Gitto
- Dipartimento di Scienze Mediche e Chirurgiche Centro di Ricerca per lo Studio delle Epatiti Università degli Studi di Bologna
Bologna
Italy
| | - Pietro Andreone
- Dipartimento di Scienze Mediche e Chirurgiche Centro di Ricerca per lo Studio delle Epatiti Università degli Studi di Bologna
Bologna
Italy
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9
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Kotha S, Neong S, Patel K. Serum biomarkers for diagnosis and monitoring viral hepatitis and hepatocellular carcinoma. Expert Rev Mol Diagn 2018; 18:713-722. [PMID: 30019978 DOI: 10.1080/14737159.2018.1496020] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Chronic liver disease due to viral hepatitis continues to be a major global health concern. Timely diagnosis and treatment will prevent cirrhosis, risk of hepatocellular carcinoma (HCC), and requirement for liver transplantation. Numerous serum biomarkers are available for viral hepatitis that are helpful in diagnosis, measuring severity, progression of disease, evaluating the best therapeutic options, and monitoring antiviral treatment response. Determining the clinical use of available diagnostic tests can be challenging for the health care provider. Areas covered: This review article attempts to summarize the established and emerging serological markers for diagnosis and managing viral hepatitis. The literature search was performed in February 2018 and included MEDLINE and Embase databases for recent relevant literature on biomarkers for viral hepatitis. Expert Commentary: Despite the discovery of several candidate biomarkers, translating these to clinical practice in viral hepatitis and HCC remains challenging. While limited availability of the new biomarkers in prevalent geographic areas and significant cost remain major obstacles, there have been exciting developments in this field. Understanding the detection limits and sensitivity of these markers and translating them into clinical use is important in management of viral hepatitis and complications of liver disease such as cirrhosis and hepatocellular cancer.
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Affiliation(s)
- Sreelakshmi Kotha
- a Department of Hepatology , Toronto General Hospital , Toronto , Canada
| | - ShuetFong Neong
- a Department of Hepatology , Toronto General Hospital , Toronto , Canada
| | - Keyur Patel
- a Department of Hepatology , Toronto General Hospital , Toronto , Canada
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10
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Baral S, Roy R, Dixit NM. Modeling how reversal of immune exhaustion elicits cure of chronic hepatitis C after the end of treatment with direct-acting antiviral agents. Immunol Cell Biol 2018; 96:969-980. [PMID: 29744934 PMCID: PMC6220890 DOI: 10.1111/imcb.12161] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2018] [Revised: 04/26/2018] [Accepted: 04/30/2018] [Indexed: 12/11/2022]
Abstract
A fraction of chronic hepatitis C patients treated with direct‐acting antivirals (DAAs) achieved sustained virological responses (SVR), or cure, despite having detectable viremia at the end of treatment (EOT). This observation, termed EOT+/SVR, remains puzzling and precludes rational optimization of treatment durations. One hypothesis to explain EOT+/SVR, the immunologic hypothesis, argues that the viral decline induced by DAAs during treatment reverses the exhaustion of cytotoxic T lymphocytes (CTLs), which then clear the infection after treatment. Whether the hypothesis is consistent with data of viral load changes in patients who experienced EOT+/SVR is unknown. Here, we constructed a mathematical model of viral kinetics incorporating the immunologic hypothesis and compared its predictions with patient data. We found the predictions to be in quantitative agreement with patient data. Using the model, we unraveled an underlying bistability that gives rise to EOT+/SVR and presents a new avenue to optimize treatment durations. Infected cells trigger both activation and exhaustion of CTLs. CTLs in turn kill infected cells. Due to these competing interactions, two stable steady states, chronic infection and viral clearance, emerge, separated by an unstable steady state with intermediate viremia. When treatment during chronic infection drives viremia sufficiently below the unstable state, spontaneous viral clearance results post‐treatment, marking EOT+/SVR. The duration to achieve this desired reduction in viremia defines the minimum treatment duration required for ensuring SVR, which our model can quantify. Estimating parameters defining the CTL response of individuals to HCV infection would enable the application of our model to personalize treatment durations.
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Affiliation(s)
- Subhasish Baral
- Department of Chemical Engineering, Indian Institute of Science, Bangalore, Karnataka, India
| | - Rahul Roy
- Department of Chemical Engineering, Indian Institute of Science, Bangalore, Karnataka, India.,Centre for Biosystems Science and Engineering, Indian Institute of Science, Bangalore, Karnataka, India.,Molecular Biophysics Unit, Indian Institute of Science, Bangalore, Karnataka, India
| | - Narendra M Dixit
- Department of Chemical Engineering, Indian Institute of Science, Bangalore, Karnataka, India.,Centre for Biosystems Science and Engineering, Indian Institute of Science, Bangalore, Karnataka, India
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11
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Ishigami M, Hayashi K, Honda T, Kuzuya T, Ishizu Y, Ishikawa T, Nakano I, Urano F, Kumada T, Yoshioka K, Hirooka Y, Goto H. Daclatasvir and asunaprevir treatment in patients infected by genotype 1b of hepatitis C virus with no or subtle resistant associated substitutions (RAS) in NS5A-Y93. J Med Virol 2018; 90:736-744. [PMID: 29111616 DOI: 10.1002/jmv.24978] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Accepted: 10/12/2017] [Indexed: 02/07/2023]
Abstract
In this study, we investigated the real-world data of the first approved interferon-free regimen in Japan, daclatasvir and asunaprevir (DCV+ASV), in chronic hepatitis C patients infected HCV genotype 1b with no or subtle amount of baseline resistant associated substitutions (RAS). Among 924 patients registered in our multicenter study, 750 patients who were proven not to be infected with NS5A-Y93H RAS by direct sequencing and to have no or subtle amount (less than 20%) of NS5A-Y93H RAS by probe assays (Cycleave or PCR invader assay) were included in this study. We investigated the anti-viral effect and factors associated with SVR12. In statistical analysis, P < 0.05 was considered as significant. The SVR12 rate in this population was 92.1% (562/618). Factors associated with SVR12 were male (odds ratio: 2.128; 95%CI: 1.134-4.000, P = 0.019); lower serum γGTP (odds ratio: 1.007; 95%CI: 1.002-1.012, P = 0.006); lower HCV-RNA (odds ratio: 1.848; 95%CI: 1.087-3.145, P = 0.023), and RVR (odds ratio: 6.250; 95%CI: 2.445-15.873, P < 0.001). No patients with γGTP ≧ 80 IU/L without RVR showed SVR12 (0/4, 0%) and one patients with γGTP ≧ 20-< 80 IU/L and HCV-RNA ≧ 6.5 logIU/mL without RVR (5/10, 50%) and two female patients with RVR but γGTP ≧ 80 IU/L and HCV-RNA ≧ 6.5 logIU/mL (7/13, 53.8%) showed a low SVR12 rate. In the present study, we showed a good viral response with DCV-ASV treatment and identified four predictive factors associated with SVR12. These four markers could be a good predictive markers for the viral effect of this treatment regimen in patients with no or subtle amount of RAS in NS5A-Y93.
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Affiliation(s)
- Masatoshi Ishigami
- Department of Gastroenterology and Hepatology, Nagoya University School of Medicine, Nagoya, Aichi, Japan
| | - Kazuhiko Hayashi
- Department of Gastroenterology and Hepatology, Nagoya University School of Medicine, Nagoya, Aichi, Japan
| | - Takashi Honda
- Department of Gastroenterology and Hepatology, Nagoya University School of Medicine, Nagoya, Aichi, Japan
| | - Teiji Kuzuya
- Department of Gastroenterology and Hepatology, Nagoya University School of Medicine, Nagoya, Aichi, Japan
| | - Yoji Ishizu
- Department of Gastroenterology and Hepatology, Nagoya University School of Medicine, Nagoya, Aichi, Japan
| | - Tetsuya Ishikawa
- Department of Gastroenterology and Hepatology, Nagoya University School of Medicine, Nagoya, Aichi, Japan
| | - Isao Nakano
- Department of Gastroenterology and Hepatology, Nagoya University School of Medicine, Nagoya, Aichi, Japan
| | - Fumihiro Urano
- Department of Gastroenterology, Toyohashi Municipal Hospital, Toyohashi, Aichi, Japan
| | - Takashi Kumada
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Gifu, Japan
| | - Kentaro Yoshioka
- Division of Liver and Biliary Diseases, Department of Internal Medicine, Fujita Health University, Toyoake, Aichi, Japan
| | - Yoshiki Hirooka
- Department of Gastroenterology and Hepatology, Nagoya University School of Medicine, Nagoya, Aichi, Japan
| | - Hidemi Goto
- Department of Gastroenterology and Hepatology, Nagoya University School of Medicine, Nagoya, Aichi, Japan
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12
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Kjellin M, Wesslén T, Löfblad E, Lennerstrand J, Lannergård A. The effect of the first-generation HCV-protease inhibitors boceprevir and telaprevir and the relation to baseline NS3 resistance mutations in genotype 1: experience from a small Swedish cohort. Ups J Med Sci 2018; 123. [PMID: 29536805 PMCID: PMC5901468 DOI: 10.1080/03009734.2018.1441928] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND The clinical experience with protease-inhibitor (PI) triple regimen appears disappointing regarding effect, side effects, high work load, and costs. This real-world study evaluates baseline and emerging resistance-associated substitutions (RASs) and their significance for treatment outcome. METHOD Thirty-six genotype 1a/b patients treated according to Swedish recommendations during 2011-2013 with triple therapy including pegylated interferon and ribavirin in combination with a protease-inhibitor, either boceprevir (BOC) or telaprevir (TVR), were retrospectively evaluated. Frozen serum samples from the patients were tested for resistance with pan-genotypic population sequencing. RESULTS Overall, 56% (20/36) of the patients achieved sustained viral response (SVR). The SVR was comparable between BOC (64%; 9/14) and TVR (50%; 11/22) (p = 0.07), and the IL28B type non-CC (48%; 12/25) and CC (46%; 6/13) (p = 0.77). The SVR was higher in patients without cirrhosis (89.5%; 17/19) (p < 0.0005), in treatment-naïve patients (70%; 14/20) (p = 0.02), and those with low viral load (<800,000 IU/mL) (66.7%; 8/12) (p < 0.0002), compared to those with cirrhosis (17.6%; 3/17), treatment-experienced (37.5%; 6/16), and high viral load (>800,000 IU/mL) (50%; 12/24). CONCLUSION PI triple regimes were highly effective in treatment-naïve patients without cirrhosis, but in this real-world cohort an inferior effect was evident in cirrhotic and treatment-experienced patients. Although tested on a limited sample, the baseline resistance testing seems to have no impact on prediction of therapy outcome. The reason could be that the baseline RASs T54S and V55A have relatively low resistance towards BOC and TVR. Emerging RASs, mainly R155K, with known high resistance to BOC and TVR were frequently found in non-responders.
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Affiliation(s)
- Midori Kjellin
- Section of Clinical Microbiology, Department of Medical Sciences, Uppsala University Hospital, Sweden
| | - Terése Wesslén
- Section of Infectious Diseases, Department of Medical Sciences, Uppsala University Hospital, Sweden
| | - Erik Löfblad
- Section of Infectious Diseases, Department of Medical Sciences, Uppsala University Hospital, Sweden
| | - Johan Lennerstrand
- Section of Clinical Microbiology, Department of Medical Sciences, Uppsala University Hospital, Sweden
| | - Anders Lannergård
- Section of Infectious Diseases, Department of Medical Sciences, Uppsala University Hospital, Sweden
- CONTACT Anders Lannergård Department of Medical Sciences, Section of Infectious Diseases, Uppsala University, S 751 85 Uppsala, Sweden
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13
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Randolph JT, Krueger AC, Donner PL, Pratt JK, Liu D, Motter CE, Rockway TW, Tufano MD, Wagner R, Lim HB, Beyer JM, Mondal R, Panchal NS, Colletti L, Liu Y, Koev G, Kati WM, Hernandez LE, Beno DWA, Longenecker KL, Stewart KD, Dumas EO, Molla A, Maring CJ. Synthesis and Biological Characterization of Aryl Uracil Inhibitors of Hepatitis C Virus NS5B Polymerase: Discovery of ABT-072, a trans-Stilbene Analog with Good Oral Bioavailability. J Med Chem 2018; 61:1153-1163. [PMID: 29342358 DOI: 10.1021/acs.jmedchem.7b01630] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
ABT-072 is a non-nucleoside HCV NS5B polymerase inhibitor that was discovered as part of a program to identify new direct-acting antivirals (DAAs) for the treatment of HCV infection. This compound was identified during a medicinal chemistry effort to improve on an original lead, inhibitor 1, which we described in a previous publication. Replacement of the amide linkage in 1 with a trans-olefin resulted in improved compound permeability and solubility and provided much better pharmacokinetic properties in preclinical species. Replacement of the dihydrouracil in 1 with an N-linked uracil provided better potency in the genotype 1 replicon assay. Results from phase 1 clinical studies supported once-daily oral dosing with ABT-072 in HCV infected patients. A phase 2 clinical study that combined ABT-072 with the HCV protease inhibitor ABT-450 provided a sustained virologic response at 24 weeks after dosing (SVR24) in 10 of 11 patients who received treatment.
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Affiliation(s)
- John T Randolph
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - A Chris Krueger
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Pamela L Donner
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - John K Pratt
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Dachun Liu
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Christopher E Motter
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Todd W Rockway
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Michael D Tufano
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Rolf Wagner
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Hock B Lim
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Jill M Beyer
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Rubina Mondal
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Neeta S Panchal
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Lynn Colletti
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Yaya Liu
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Gennadiy Koev
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Warren M Kati
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Lisa E Hernandez
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - David W A Beno
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Kenton L Longenecker
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Kent D Stewart
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Emily O Dumas
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Akhteruzzaman Molla
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Clarence J Maring
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
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14
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Rosenthal E, Fougerou-Leurent C, Renault A, Carrieri MP, Marcellin F, Garraffo R, Teicher E, Aumaitre H, Lacombe K, Bailly F, Billaud E, Chevaliez S, Dominguez S, Valantin MA, Reynes J, Naqvi A, Cotte L, Metivier S, Leroy V, Dupon M, Allegre T, De Truchis P, Jeantils V, Chas J, Salmon-Ceron D, Morlat P, Neau D, Perré P, Piroth L, Pol S, Bourlière M, Pageaux GP, Alric L, Zucman D, Girard PM, Poizot-Martin I, Yazdanpanah Y, Raffi F, Pabic EL, Tual C, Pailhé A, Amri I, Bellissant E, Molina JM. Efficacy, safety and patient-reported outcomes of ledipasvir/sofosbuvir in NS3/4A protease inhibitor-experienced individuals with hepatitis C virus genotype 1 and HIV coinfection with and without cirrhosis (ANRS HC31 SOFTRIH study). HIV Med 2017; 19:227-237. [PMID: 29214737 DOI: 10.1111/hiv.12571] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/19/2017] [Indexed: 12/26/2022]
Abstract
OBJECTIVES Studies evaluating the efficacy and safety of the fixed-dose combination ledipasvir (LDV)/sofosbuvir (SOF) in patients coinfected with HIV-1 and hepatitis C virus (HCV) have mainly included treatment-naïve patients without cirrhosis. We aimed to evaluate the efficacy and safety of this combination in treatment-experienced patients with and without cirrhosis. METHODS We conducted a multicentre, open-label, double-arm, nonrandomized study in patients coinfected with HIV-1 and HCV genotype 1 with and without cirrhosis, who had good viral suppression on their antiretroviral regimens. All patients were pretreated with a first-generation NS3/4A protease inhibitor (PI) plus pegylated interferon/ribavirin. Patients received a fixed-dose combination of LDV/SOF for 12 weeks, or for 24 weeks if cirrhosis was present. The primary endpoint was a sustained virological response (SVR) 12 weeks after the end of therapy. Secondary endpoints included safety, pharmacokinetics and patient-reported outcomes. RESULTS Of the 68 patients enrolled, 39.7% had cirrhosis. Sixty-five patients [95.6%; 95% confidence interval (CI): 87.6-99.1%; P < 0.0001] achieved an SVR, with similar rates of SVR in those with and without cirrhosis. Tolerance was satisfactory, with mainly grade 1 or 2 adverse events. Among patient-reported outcomes, only fatigue significantly decreased at the end of treatment compared with baseline [odds ratio (OR): 0.36; 95% CI: 0.14-0.96; P = 0.04]. Mean tenofovir area under the plasma concentration-time curve (AUC) at week 4 was high, with mean ± SD AUC variation between baseline and week 4 higher in cirrhotic than in noncirrhotic patients (3261.57 ± 1920.47 ng/mL vs. 1576.15 ± 911.97 ng/mL, respectively; P = 0.03). Mild proteinuria (54.4%), hypophosphataemia (50.0%), blood bicarbonate decrease (29.4%) and hypokalaemia (13.2%) were reported. The serum creatinine level was not modified. CONCLUSIONS LDV/SOF provided a high SVR rate in PI-experienced subjects coinfected with HCV genotype 1 and HIV-1, including patients with cirrhosis.
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Affiliation(s)
- E Rosenthal
- Internal Medicine Department, CHU de Nice, Hôpital Archet 1, Nice, France
| | - C Fougerou-Leurent
- Pharmacology Department, CHU Rennes, Rennes, France.,Inserm, CIC1414, Rennes, France
| | - A Renault
- Inserm, CIC1414, Rennes, France.,Pharmacology Laboratory, Faculté de Médecine, Univ Rennes 1, Rennes, France
| | - M P Carrieri
- Sciences Economiques & Sociales de la Santé & Traitement de l'Information Médicale, Inserm, IRD, Aix Marseille Univ, Marseille, France.,Observatoire Régional de la Santé Provence-Alpes-Côte d'Azur, Marseille, France
| | - F Marcellin
- Sciences Economiques & Sociales de la Santé & Traitement de l'Information Médicale, Inserm, IRD, Aix Marseille Univ, Marseille, France.,Observatoire Régional de la Santé Provence-Alpes-Côte d'Azur, Marseille, France
| | - R Garraffo
- Clinical Pharmacology and Toxicology Department, CHU de Nice, Nice, France
| | - E Teicher
- Infectious Diseases Department, APHP, Hôpital Bicêtre, Le Kremlin Bicêtre, France
| | - H Aumaitre
- Infectious and Tropical Diseases Department, Hôpital de Perpignan, Perpignan, France
| | - K Lacombe
- Infectious Diseases Department, APHP, Hôpital Saint Antoine, Paris, France
| | - F Bailly
- Hepatology Department, HCL, Hôpital de la Croix-Rousse, Lyon, France
| | - E Billaud
- Infectious Diseases Department, CHU Nantes, Nantes, France
| | - S Chevaliez
- Virology Department, APHP, Hôpital Henri Mondor, Créteil, France
| | - S Dominguez
- Clinical Immunology Department, APHP, Hôpital Henri Mondor, Créteil, France
| | - M A Valantin
- Infectious Diseases Department, APHP, Hôpital La Pitié Salpêtrière, Paris, France
| | - J Reynes
- Infectious Diseases Department, CHU Montpellier, Montpellier, France
| | - A Naqvi
- Infectious Diseases Department, CHU de Nice, Hôpital Archet 1, Nice, France
| | - L Cotte
- Infectious Diseases Department, HCL, Hôpital de la Croix-Rousse, Lyon, France
| | - S Metivier
- Hepatogastroenterology Department, CHU Toulouse, Toulouse, France
| | - V Leroy
- Hepatogastroenterology Department, CHU Grenoble, Grenoble, France
| | - M Dupon
- Infectious Diseases Department, CHU Bordeaux, Bordeaux, France
| | - T Allegre
- Hemato Oncology Department, CH du Pays d'Aix, Aix-en-Provence, France
| | - P De Truchis
- Infectious Diseases Department, APHP, Hôpital R Poincaré, Garches, France
| | - V Jeantils
- Infectious Diseases Department, APHP, Hôpital J Verdier, Bondy, France
| | - J Chas
- Infectious and Tropical Diseases Department, APHP, Hôpital Tenon, Paris, France
| | - D Salmon-Ceron
- Infectious Diseases Department, APHP, Hôpital Cochin, Paris, France
| | - P Morlat
- Internal Medicine and Infectious Diseases Department, CHU Bordeaux, Bordeaux, France
| | - D Neau
- Infectious and Tropical Diseases Department, CHU Bordeaux, Bordeaux, France
| | - P Perré
- Internal Medicine Department, CHD Vendée, La Roche sur Yon, France
| | - L Piroth
- Infectious Diseases Department, CHU Dijon, Dijon, France
| | - S Pol
- Hepato-Gastroenterology Department, APHP, Hôpital Cochin, Paris, France
| | - M Bourlière
- Hepatogastroenterology Department, Hôpital Saint Joseph, Marseille, France
| | - G P Pageaux
- Hepatogastroenterology Department, CHU Montpellier, Montpellier, France
| | - L Alric
- Internal Medicine Department, CHU Toulouse, Toulouse, France
| | - D Zucman
- Internal Medicine Department, Hôpital Foch, Suresne, France
| | - P M Girard
- Infectious Diseases Department, APHP, Hôpital Saint Antoine, Paris, France
| | - I Poizot-Martin
- Immuno and Clinical Hematology department, APHM Sainte-Marguerite, Aix Marseille Univ, Marseille, France.,Inserm U912 (SESSTIM), Marseille, France
| | - Y Yazdanpanah
- Infectious and Tropical Diseases Department, APHP, Hôpital Bichat, Paris, France
| | - F Raffi
- Infectious Diseases Department, CHU Nantes, Nantes, France
| | - E Le Pabic
- Pharmacology Department, CHU Rennes, Rennes, France.,Inserm, CIC1414, Rennes, France
| | - C Tual
- Pharmacology Department, CHU Rennes, Rennes, France.,Inserm, CIC1414, Rennes, France
| | - A Pailhé
- Unité de Recherche Clinique et Fondamentale sur les Hépatites Virales, ANRS (France Recherche Nord & Sud Sida-hiv Hépatites), Paris, France
| | - I Amri
- Unité de Recherche Clinique et Fondamentale sur les Hépatites Virales, ANRS (France Recherche Nord & Sud Sida-hiv Hépatites), Paris, France
| | - E Bellissant
- Pharmacology Department, CHU Rennes, Rennes, France.,Inserm, CIC1414, Rennes, France.,Pharmacology Laboratory, Faculté de Médecine, Univ Rennes 1, Rennes, France
| | - J M Molina
- Hepatogastroenterology Department, APHP, Hôpital Saint Louis, Paris, France
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15
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Loggi E, Galli S, Vitale G, Di Donato R, Vukotic R, Grandini E, Margotti M, Guarneri V, Furlini G, Galli C, Re MC, Andreone P. Monitoring the treatment of hepatitis C with directly acting antivirals by serological and molecular methods. PLoS One 2017; 12:e0187755. [PMID: 29125869 PMCID: PMC5681287 DOI: 10.1371/journal.pone.0187755] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 10/25/2017] [Indexed: 12/16/2022] Open
Abstract
AIM To evaluate the potential value of using a serological assay to quantitate the hepatitis C virus core antigen (HCV-Ag) when monitoring patients with chronic hepatitis C being treated with direct-acting antivirals (DAAs). METHODS Ninety-six patients treated with DAAs, either alone (91) or in combination with PEG interferon (5), were tested for HCV-RNA and for HCV-Ag at baseline and at weeks 2, 4, 8 and 12 during treatment and 12 weeks after completion. The concordance and correlation between the viral parameters as well as the respective kinetics during and after treatment were evaluated. RESULTS A sustained viral response (SVR) was achieved in 82 patients (91%), whereas 11 relapsed (R) and 1 showed a virological breakthrough while receiving treatment. HCV-RNA and HCV-Ag showed good concordance (kappa = 0.62) and correlation. No significant differences between SVR and R was observed in either assay at 2 and 4 weeks after the start of treatment. At 8 weeks, HCV-Ag showed higher accuracy than HCV-RNA (AUC: 0.74 vs. 0.55) and there was a significantly greater decrease from baseline in SVR than in R (4.01 vs. 3.36 log10; p<0.05). CONCLUSIONS Monitoring during treatment with DAAs by using either HCV-RNA or HCV-Ag has only a limited predictive value for SVR. Since those assays are equivalent for identifying a virological relapse, HCV-Ag may be preferred from an economical and organizational perspective.
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Affiliation(s)
- Elisabetta Loggi
- Dipartimento di Scienze Mediche e Chirurgiche, Centro di Ricerca per lo Studio delle Epatiti, Università degli Studi di Bologna, Bologna, Italy
| | - Silvia Galli
- Unità di Microbiologia, Policlinico S.Orsola-Malpighi, Bologna, Italy
| | - Giovanni Vitale
- Dipartimento di Scienze Mediche e Chirurgiche, Centro di Ricerca per lo Studio delle Epatiti, Università degli Studi di Bologna, Bologna, Italy
| | - Roberto Di Donato
- Dipartimento di Scienze Mediche e Chirurgiche, Centro di Ricerca per lo Studio delle Epatiti, Università degli Studi di Bologna, Bologna, Italy
| | - Ranka Vukotic
- Dipartimento di Scienze Mediche e Chirurgiche, Centro di Ricerca per lo Studio delle Epatiti, Università degli Studi di Bologna, Bologna, Italy
| | - Elena Grandini
- Dipartimento di Scienze Mediche e Chirurgiche, Centro di Ricerca per lo Studio delle Epatiti, Università degli Studi di Bologna, Bologna, Italy
| | - Marzia Margotti
- Dipartimento di Scienze Mediche e Chirurgiche, Centro di Ricerca per lo Studio delle Epatiti, Università degli Studi di Bologna, Bologna, Italy
| | - Valeria Guarneri
- Dipartimento di Scienze Mediche e Chirurgiche, Centro di Ricerca per lo Studio delle Epatiti, Università degli Studi di Bologna, Bologna, Italy
| | - Giuliano Furlini
- Unità di Microbiologia, Policlinico S.Orsola-Malpighi, Bologna, Italy
| | - Claudio Galli
- Medical Scientific Liaison, Abbott Diagnostics, Roma, Italy
| | - Maria Carla Re
- Unità di Microbiologia, Policlinico S.Orsola-Malpighi, Bologna, Italy
| | - Pietro Andreone
- Dipartimento di Scienze Mediche e Chirurgiche, Centro di Ricerca per lo Studio delle Epatiti, Università degli Studi di Bologna, Bologna, Italy
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16
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Ishigami M, Hayashi K, Honda T, Kuzuya T, Ishizu Y, Ishikawa T, Nakano I, Urano F, Kumada T, Yoshioka K, Goto H, Hirooka Y. Daclatasvir and asunaprevir treatment in patients with severe liver fibrosis by hepatitis C virus genotype 1b infection: Real-world data. J Gastroenterol Hepatol 2017; 32:1879-1886. [PMID: 28258705 DOI: 10.1111/jgh.13779] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Revised: 02/22/2017] [Accepted: 02/28/2017] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND AIM In this study, we investigated the real-world data of the first approved interferon-free regimen in Japan: daclatasvir and asunaprevir in chronic hepatitis C patients with severe fibrosis. METHODS Among 924 patients registered in our multicenter study, 535 patients were defined as having severe fibrosis with Fib-4 index ≧ 3.25 and were included in this study. We investigated antiviral effect and factors associated with sustained viral response 12 (SVR12), and the additional effects on serum α-fetoprotein and albumin levels by eradicating virus in patients who attained SVR were investigated. In statistical analysis, P < 0.05 was considered as significant levels. RESULTS Antiviral effect was lower in patients with severe fibrosis at 8 and 12 weeks after start of the treatment (96.3%, 97.1% with severe fibrosis vs 99.5%, 99.2% without severe fibrosis, P = 0.002 and P = 0.036, respectively), and more early relapse (SVR4; 90.4% with severe fibrosis vs 95.4% without fibrosis, P = 0.008) was seen in patients with severe fibrosis; however, there were no differences in SVR12 and SVR24. In the safety profiles, discontinuation rate due to liver injury (2.8% with severe fibrosis vs 3.3% without severe fibrosis) or other causes of discontinuation was not different between two groups. Serum α-fetoprotein significantly decreased, and serum albumin levels significantly increased as early as 4 weeks after the start of treatment. CONCLUSION Although the antiviral effect was slightly lower in patients with severe fibrosis compared with those without, treatment with daclatasvir and asunaprevir is basically an effective and well-tolerable treatment in these populations.
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Affiliation(s)
- Masatoshi Ishigami
- Department of Gastroenterology and Hepatology, School of Medicine, Nagoya University, Nagoya, Japan
| | - Kazuhiko Hayashi
- Department of Gastroenterology and Hepatology, School of Medicine, Nagoya University, Nagoya, Japan
| | - Takashi Honda
- Department of Gastroenterology and Hepatology, School of Medicine, Nagoya University, Nagoya, Japan
| | - Teiji Kuzuya
- Department of Gastroenterology and Hepatology, School of Medicine, Nagoya University, Nagoya, Japan
| | - Yoji Ishizu
- Department of Gastroenterology and Hepatology, School of Medicine, Nagoya University, Nagoya, Japan
| | - Tetsuya Ishikawa
- Department of Gastroenterology and Hepatology, School of Medicine, Nagoya University, Nagoya, Japan
| | - Isao Nakano
- Department of Gastroenterology and Hepatology, School of Medicine, Nagoya University, Nagoya, Japan
| | - Fumihiro Urano
- Department of Gastroenterology, Toyohashi Municipal Hospital, Toyohashi, Japan
| | - Takashi Kumada
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Kentaro Yoshioka
- Division of Liver and Biliary Diseases, Department of Internal Medicine, Fujita Health University, Toyoake, Japan
| | - Hidemi Goto
- Department of Gastroenterology and Hepatology, School of Medicine, Nagoya University, Nagoya, Japan
| | - Yoshiki Hirooka
- Department of Gastroenterology and Hepatology, School of Medicine, Nagoya University, Nagoya, Japan
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Nguyen THT, Guedj J, Uprichard SL, Kohli A, Kottilil S, Perelson AS. The paradox of highly effective sofosbuvir-based combination therapy despite slow viral decline: can we still rely on viral kinetics? Sci Rep 2017; 7:10233. [PMID: 28860456 PMCID: PMC5579268 DOI: 10.1038/s41598-017-09776-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Accepted: 07/28/2017] [Indexed: 02/07/2023] Open
Abstract
High sustained virologic response (SVR) rates have been observed after 6 weeks of anti-HCV treatment using sofosbuvir, ledipasvir and a non-nucleoside polymerase-inhibitor (GS-9669) or a protease-inhibitor (GS-9451) and after 12 weeks with sofosbuvir + ledipasvir. Here we analyze the viral kinetics observed during these treatments to decipher the origin of the rapid cure and to evaluate the possibility of further reducing treatment duration. We found that viral kinetics were surprisingly slow in all treatment groups and could not reproduce the high SVR rates observed. Based on experimental results suggesting that NS5A- or protease-inhibitors can generate non-infectious virus, we incorporated this effect into a mathematical model. We found that to predict observed SVR rates it was necessary to assume that ledipasvir, GS-9669 and GS-9451 rapidly reduce virus infectivity. We predicted with this model that 4 weeks of triple therapy could be sufficient to achieve SVR in patients with undetectable viremia at week 1, but would be suboptimal in general. In conclusion, the rapid cure rate achieved with these combinations is largely disconnected from viral loads measured during treatment. A model assuming that rapid cure is due to a drug effect of generating non-infectious virus could be a basis for future response guided therapy.
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Affiliation(s)
- Thi Huyen Tram Nguyen
- IAME, UMR 1137, INSERM, F-75018 Paris, France; Univ Paris Diderot, Sorbonne Paris Cité, F-75018, Paris, France
| | - Jérémie Guedj
- IAME, UMR 1137, INSERM, F-75018 Paris, France; Univ Paris Diderot, Sorbonne Paris Cité, F-75018, Paris, France. .,Hopital Henri Mondor, Université Paris-Est, Creteil, France.
| | - Susan L Uprichard
- Department of Medicine, Loyola University Medical Center, Maywood, Illinois, USA
| | - Anita Kohli
- Dignity Health, St. Joseph's Hospital, Phoenix, Arizona, USA
| | - Shyam Kottilil
- Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD, USA
| | - Alan S Perelson
- Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM, USA
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18
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Lamoury FMJ, Soker A, Martinez D, Hajarizadeh B, Cunningham EB, Cunningham P, Bruggmann P, Foster GR, Dalgard O, Backmund M, Conway B, Robaeys G, Swan T, Cloherty G, Marks P, Grebely J, Dore GJ, Applegate TL. Hepatitis C virus core antigen: A simplified treatment monitoring tool, including for post-treatment relapse. J Clin Virol 2017; 92:32-38. [PMID: 28521211 DOI: 10.1016/j.jcv.2017.05.007] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Revised: 04/18/2017] [Accepted: 05/06/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND Simple, affordable diagnostic tools are essential to facilitate global hepatitis C virus (HCV) elimination efforts. OBJECTIVES This study evaluated the clinical performance of core antigen (HCVcAg) assay from plasma samples to monitor HCV treatment efficacy and HCV viral recurrence. STUDY DESIGN Plasma samples from a study of response-guided pegylated-interferon/ribavirin therapy for people who inject drugs with chronic HCV genotype 2/3 infection were assessed for HCV RNA (AmpliPrep/COBAS Taqman assay, Roche) and HCVcAg (ARCHITECT HCV Ag, Abbott Diagnostics) during and after therapy. The sensitivity and specificity of the HCVcAg assay was compared to the HCV RNA assay (gold standard). RESULTS A total of 335 samples from 92 enrolled participants were assessed (mean 4 time-points per participant). At baseline, end of treatment response (ETR) and sustained virological response (SVR) visits, the sensitivity of the HCVcAg assay with quantifiable HCV RNA threshold was 94% (95% CI: 88%, 98%), 56% (21%, 86%) and 100%, respectively. The specificity was between 98 to 100% for all time-points assessed. HCVcAg accurately detected all six participants with viral recurrence, demonstrating 100% sensitivity and specificity. One participant with detectable (non-quantifiable) HCV RNA and non-reactive HCVcAg at SVR12 subsequently cleared HCV RNA at SVR24. CONCLUSIONS HCVcAg demonstrated high sensitivity and specificity for detection of pre-treatment and post-treatment viraemia. This study indicates that confirmation of active HCV infection, including recurrent viraemia, by HCVcAg is possible. Reduced on-treatment sensitivity of HCVcAg may be a clinical advantage given the moves toward simplification of monitoring schedules.
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Affiliation(s)
| | | | | | | | | | - Philip Cunningham
- St. Vincent's Applied Medical Research, Darlinghurst, Sydney, Australia
| | | | - Graham R Foster
- Queen Mary University of London, Institute of Cell and Molecular Science, London, UK
| | - Olav Dalgard
- Department of Infectious Diseases, Akershus University Hospital, Lørenskog, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Markus Backmund
- Department of Addiction Medicine, Munich-Schwabing Hospital, Munich, Germany
| | - Brian Conway
- Department of Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada
| | - Geert Robaeys
- Department of Gastroenterology and Hepatology, Ziekenhuis Oost-Limburg, Schiepse, Belgium; Faculty of Medicine and Life Sciences, Limburg Clinical Research Program, Belgium; Department of Hepatology UZ Leuven, Leuven, Belgium
| | - Tracy Swan
- Department of Gastroenterology and Hepatology, Ziekenhuis Oost-Limburg, Schiepse, Belgium
| | | | - Pip Marks
- The Kirby Institute, UNSW Sydney, Sydney, Australia
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19
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Vermehren J, Bourlière M, Pol S, Marcellin P, Hyland RH, Jiang D, Brainard DM, Zeuzem S, Welzel TM. Comparison of on-treatment HCV RNA during direct antiviral therapy using two different COBAS TaqMan HCV assays. J Clin Virol 2017; 89:51-56. [PMID: 28259054 DOI: 10.1016/j.jcv.2017.02.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2016] [Revised: 01/20/2017] [Accepted: 02/17/2017] [Indexed: 12/23/2022]
Abstract
BACKGROUND Repeated measurements of hepatitis C virus (HCV) RNA levels during antiviral therapy are recommended to monitor treatment efficacy and adherence. Throughout most direct antiviral agent (DAA) approval studies, HCV RNA cutoffs and endpoints were established with the COBAS TaqMan assay for use with the High Pure System (HPS/CTM). Different assays used in clinical practice may yield different quantitative results and possibly impact treatment decisions. OBJECTIVES The concordance of the fully-automated COBAS AmpliPrep/COBAS TaqMan assay (CAP/CTM) with HPS/CTM and its ability to predict response to DAA-treatment with ledipasvir/sofosbuvir was assessed in cirrhotic patients with HCV genotype-1-infection who had failed prior treatment with protease inhibitor-based regimens. STUDY DESIGN Serum samples from patients (n=154) treated in the phase-2 SIRIUS-study were collected at baseline and during antiviral therapy (weeks 1-8), and were tested in parallel by both assays. RESULTS The mean difference between HPS/CTM and CAP/CTM at baseline (n=153) was 0.32 log10 IU/mL HCV RNA. Discordant results were observed in 12% of samples collected at treatment weeks 1-8, with the greatest differences observed at weeks 2 and 4 (14% and 29%, respectively, for undetectable HCV RNA). SVR rates were 96%-97% in the study and were not significantly different between patients with detectable vs. undetectable HCV RNA according to both assays at weeks 1-4 of antiviral therapy. CONCLUSIONS CAP/CTM and HPS/CTM showed significantly different response rates during the early stages of ledipasvir/sofosbuvir treatment. However, on-treatment response was not predictive of SVR with either assay, indicating that determination of on-treatment HCV RNA levels may not be useful to guide treatment decisions.
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Affiliation(s)
- Johannes Vermehren
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany.
| | - Marc Bourlière
- Hépato-Gastroénterologie, Hôpital-Saint Joseph, Marseille, France
| | - Stanislas Pol
- Hépatologie, Université Paris Descartes, Inserm UMS20, Institut Pasteur, Hôpital Cochin, France
| | | | - Robert H Hyland
- Liver Disease Therapeutic Area, Gilead Sciences, Foster City, CA, USA
| | - Deyuan Jiang
- Liver Disease Therapeutic Area, Gilead Sciences, Foster City, CA, USA
| | - Diana M Brainard
- Liver Disease Therapeutic Area, Gilead Sciences, Foster City, CA, USA
| | - Stefan Zeuzem
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | - Tania M Welzel
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany.
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20
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Smolders EJ, Pape S, de Kanter CTMM, van den Berg AP, Drenth JPH, Burger DM. Decreased tacrolimus plasma concentrations during HCV therapy: a drug-drug interaction or is there an alternative explanation? Int J Antimicrob Agents 2017; 49:379-382. [PMID: 28185946 DOI: 10.1016/j.ijantimicag.2016.12.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Revised: 11/23/2016] [Accepted: 12/03/2016] [Indexed: 12/13/2022]
Abstract
Chronic hepatitis C virus (HCV) infection can cause severe liver cirrhosis, for which liver transplantation is the only therapy. To prevent organ rejection, transplanted patients are treated with immunosuppressive agents. We describe two transplanted patients treated with tacrolimus who were simultaneously treated with direct-acting antivirals (DAAs) for their chronic HCV infection. No pharmacokinetic drug-drug interactions (DDIs) were expected between tacrolimus and the selected DAAs. However, in both patients, tacrolimus plasma concentrations decreased during HCV treatment. We hypothesise that decreased plasma concentrations were not caused by a DDI but were an indirect result of the clearance of the HCV infection. During chronic HCV infection, pro-inflammatory cytokines may inhibit cytochrome P450 (CYP) enzymes, which are primarily responsible for tacrolimus metabolism. If this is true, then with clearance of the virus the activity of these enzymes will normalise and tacrolimus metabolism will increase. These changes were clinically relevant because the tacrolimus dosage needed to be adjusted. Therefore, physicians should be aware that CYP substrates with narrow therapeutic ranges might require dose adaption during HCV therapy with DAAs.
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Affiliation(s)
- E J Smolders
- Department of Pharmacy, radboud university medical center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands.
| | - S Pape
- Department of Gastroenterology and Hepatology, radboud university medical center, Nijmegen, The Netherlands
| | - C T M M de Kanter
- Department of Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands
| | - A P van den Berg
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
| | - J P H Drenth
- Department of Gastroenterology and Hepatology, radboud university medical center, Nijmegen, The Netherlands
| | - D M Burger
- Department of Pharmacy, radboud university medical center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands
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21
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Malespin M, Benyashvili T, Uprichard SL, Perelson AS, Dahari H, Cotler SJ. Prevalence of end of treatment RNA-positive/sustained viral response in HCV patients treated with sofosbuvir combination therapies. Therap Adv Gastroenterol 2017; 10:68-73. [PMID: 28286560 PMCID: PMC5330612 DOI: 10.1177/1756283x16672392] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Some chronic hepatitis C virus (HCV), genotype 1 infected patients treated with direct antiviral agents (DAAs) remain viremic at end of treatment (EOT+), yet go on to achieve sustained virological response 12 weeks after completion of therapy (SVR12). The incidence of EOT+/SVR in patients with genotype 1 and other genotypes, as well as whether such patients achieve SVR24 remain in question. The aims of this study were to evaluate the frequency and durability of EOT+/SVR12&24 and other response categories in HCV genotype 1, 2, or 3 infected patients treated with DAA in clinical practice. METHODS Data from patients treated with all oral sofosbuvir-based regimens at a university hepatology practice by 1 July 2015 were reviewed retrospectively. Responses were categorized based on virus levels during and post DAA treatment. HCV RNA levels were measured by Abbott RealTime HCV (ART) or by Roche CobasTaqMan v2.0 (RCTM) assays. RESULTS The study population included 89 patients. Participants were 62% genotype 1, 19% genotype 2 and 19% genotype 3, 54% cirrhotic and 46% treatment-experienced. A total of 45 received sofosbuvir-simeprevir, 38 sofosbuvir-ribavirin and 6 sofosbuvir-ledipasvir. The SVR12 rate was 82%. A total of 5 patients (6%), all with genotype 1, had EOT+ by ART assay and each achieved SVR12&24. CONCLUSIONS A total of 9% of genotype 1 patients (6% overall) treated with DAAs were EOT+ by ART and all EOT+ cases achieved SVR24. EOT+/SVR was not observed with genotype 2 or 3 or by the RCTM assay. In patients treated with DAAs, EOT+ by the ART assay does not indicate treatment failure.
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Affiliation(s)
| | - Tamara Benyashvili
- Program for Experimental and Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA
| | - Susan L. Uprichard
- Program for Experimental and Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA
| | - Alan S. Perelson
- Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM, USA
| | - Harel Dahari
- Program for Experimental and Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA
| | - Scott J. Cotler
- Program for Experimental and Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA
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22
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Kowdley KV, Nelson DR, Lalezari JP, Box T, Gitlin N, Poleynard G, Rabinovitz M, Ravendhran N, Sheikh AM, Siddique A, Bhore R, Noviello S, Rana K. On-treatment HCV RNA as a predictor of sustained virological response in HCV genotype 3-infected patients treated with daclatasvir and sofosbuvir. Liver Int 2016; 36:1611-1618. [PMID: 27188960 DOI: 10.1111/liv.13165] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Accepted: 05/13/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Many currently available direct-acting antiviral (DAA) regimens are less effective against HCV genotype 3 than against other HCV genotypes. The all-oral, pangenotypic DAA combination of daclatasvir (NS5A inhibitor) + sofosbuvir (nucleotide NS5B inhibitor) was studied in genotype 3-infected treatment-naive and -experienced patients (ALLY-3) who achieved rates of sustained virological response at post-treatment Week 12 (SVR12) of 90 and 86% respectively. In this analysis, we assessed whether on-treatment responses to daclatasvir + sofosbuvir in genotype 3-infected patients could predict treatment outcome. METHODS In ALLY-3, treatment-naive and -experienced patients, with or without cirrhosis, were treated with daclatasvir + sofosbuvir for 12 weeks. HCV RNA kinetics and categorical virological responses on treatment were assessed. The proportions of responders and nonresponders by study week, and time to first undetectable HCV RNA, were analysed for utility in predicting treatment outcome. RESULTS Overall, HCV RNA levels declined rapidly during Week 1 of treatment in both treatment-naive and -experienced cohorts. Although patients with cirrhosis had a slower initial virological response as measured by the proportion of patients with HCV RNA below the lower limit of quantification at Week 1, responses converged thereafter. Positive and negative predictive values calculated for on-treatment responses were generally comparable with the overall SVR12 rate and were therefore limited indicators of outcome. SVR12 rates were not impacted by time to first undetectable HCV RNA. CONCLUSIONS On-treatment responses are not useful predictors of ultimate virological response to the daclatasvir + sofosbuvir regimen.
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Affiliation(s)
| | | | | | - Terry Box
- Clinical Research Centers of America, LLC, Murray, UT, USA
| | - Norman Gitlin
- Atlanta Gastroenterology Associates, Atlanta, GA, USA
| | | | | | | | - Aasim M Sheikh
- Gastrointestinal Specialists of Georgia, Marietta, GA, USA
| | | | - Rafia Bhore
- Bristol-Myers Squibb Research and Development, Princeton, NJ, USA
| | | | - Khurram Rana
- Bristol-Myers Squibb Research and Development, Wallingford, CT, USA
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23
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Cloherty G, Chevaliez S, Sarrazin C, Herman C, Holzmayer V, Dawson G, Maasoumy B, Vermehren J, Wedemeyer H, Feld JJ, Pawlotsky JM. Hepatitis C RNA assay differences in results: Potential implications for shortened therapy and determination of Sustained Virologic Response. Sci Rep 2016; 6:35410. [PMID: 27762283 PMCID: PMC5071881 DOI: 10.1038/srep35410] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Accepted: 09/28/2016] [Indexed: 12/17/2022] Open
Abstract
Approval of Ledipasvir/Sofosbuvir for the treatment of chronic hepatitis C (HCV) includes the truncation of therapy from 12 to 8 weeks in treatment naïve, non-cirrhotic patients with baseline HCV RNA levels <6 million IU/mL (6.8 log10 IU/mL). The aim of this study was to evaluate this clinical cutoff with a different widely used commercially available HCV RNA test. Results from samples tested prospectively with Roche High Pure TaqMan HCV 2.0 test (HPS) were compared to those tested retrospectively with the Abbott RealTime HCV RNA test (ART). Using 6 million IU/mL as the cut-off, pre-treatment results were concordant in 70.4% of cases. When results with the same test measured at screening and baseline, clinical decisions could be impacted in 14.4% and 6.2% of cases for HPS and ART respectively. Using only HCV RNA cutoff of 6 million IU/mL, 29.55% of subjects would receive a different and potentially incorrect treatment duration based solely on HCV RNA test method used. A further 6-14% of subjects would have treatment decision change based on the day the sample was taken.
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Affiliation(s)
| | - Stephane Chevaliez
- National Reference Center for Viral Hepatitis B, C and delta, Hopital Henry Mondor, Université Paris-Est, Créteil, France
| | - Christoph Sarrazin
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | | | | | | | - Benjamin Maasoumy
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Germany
| | - Johannes Vermehren
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Germany
| | - Heiner Wedemeyer
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | - Jordan J Feld
- Toronto Centre for Liver Disease, Sandra Rotman Centre for Global Health, University of Toronto, Toronto, ON, Canada
| | - Jean-Michel Pawlotsky
- National Reference Center for Viral Hepatitis B, C and delta, Hopital Henry Mondor, Université Paris-Est, Créteil, France
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24
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Maasoumy B, Vermehren J. Diagnostics in hepatitis C: The end of response-guided therapy? J Hepatol 2016; 65:S67-S81. [PMID: 27641989 DOI: 10.1016/j.jhep.2016.07.023] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Revised: 07/20/2016] [Accepted: 07/21/2016] [Indexed: 02/07/2023]
Abstract
On-treatment hepatitis C virus (HCV) RNA has been used to predict response to interferon (IFN)-based therapy. The concept of response-guided treatment (RGT) was established to determine optimal treatment duration and to early identify patients not responding to futile therapies. RGT helped to improve sustained virologic response (SVR) rates and lower the rates of adverse effects. RGT was of particular importance for telaprevir- and boceprevir-based triple therapies. RGT strategies are dependent on highly sensitive and reproducible HCV RNA quantification. However, different HCV RNA assays are used in routine clinical practice and these differ significantly in their performance characteristics. The development of IFN-free therapies has fundamentally changed the role of on-treatment HCV RNA for SVR prediction. Given the high efficacy and excellent tolerability of IFN-free regimens, the interest in treatment individualization has decreased. However, shorter treatment durations may still be desirable, particularly with respect to the high costs of current IFN-free direct-acting antiviral agents (DAAs). Moreover, some difficult-to-treat patients remain, e.g., those infected with HCV genotype 3 in whom the current standard of care may not always be sufficient to achieve SVR, especially in treatment-experienced patients with cirrhosis. Here, a RGT extension may be feasible. However, current data on the predictive value of on-treatment HCV RNA are limited and have shown conflicting results. As more potent DAAs become available, the role of response prediction may diminish further. Currently, shorter treatment duration is only based on baseline HCV RNA whereas no RGT strategy is recommended for any of the approved DAA regimens available.
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Affiliation(s)
- Benjamin Maasoumy
- Medizinische Hochschule Hannover, Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Hannover, Germany
| | - Johannes Vermehren
- Universitätsklinikum Frankfurt, Medizinische Klinik 1, Frankfurt am Main, Germany.
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25
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Dustin LB, Bartolini B, Capobianchi MR, Pistello M. Hepatitis C virus: life cycle in cells, infection and host response, and analysis of molecular markers influencing the outcome of infection and response to therapy. Clin Microbiol Infect 2016; 22:826-832. [PMID: 27592089 PMCID: PMC5627509 DOI: 10.1016/j.cmi.2016.08.025] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2016] [Revised: 08/16/2016] [Accepted: 08/25/2016] [Indexed: 12/13/2022]
Abstract
Hepatitis C virus (HCV) is a major global health burden accounting for around 170 million chronic infections worldwide. Since its discovery, which dates back to about 30 years ago, many details of the viral genome organization and the astonishing genetic diversity have been unveiled but, owing to the difficulty of culturing HCV in vitro and obtaining fully susceptible yet immunocompetent in vivo models, we are still a long way from the full comprehension of viral life cycle, host cell pathways facilitating or counteracting infection, pathogenetic mechanisms in vivo, and host defences. Here, we illustrate the viral life cycle into cells, describe the interplay between immune and genetic host factors shaping the course of infection, and provide details of the molecular approaches currently used to genotype, monitor replication in vivo, and study the emergence of drug-resistant viral variants.
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Affiliation(s)
- L B Dustin
- Kennedy Institute for Rheumatology and Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK
| | - B Bartolini
- Laboratory of Virology, National Institute for Infectious Diseases "Lazzaro Spallanzani" IRCCS, Rome, Italy
| | - M R Capobianchi
- Laboratory of Virology, National Institute for Infectious Diseases "Lazzaro Spallanzani" IRCCS, Rome, Italy
| | - M Pistello
- Virology Unit, Pisa University Hospital, and Virology Section and Retrovirus Centre, Department of Translational Research, University of Pisa, Pisa, Italy.
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26
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Dahari H, Halfon P, Cotler SJ. Resurrection of response-guided therapy for sofosbuvir combination therapies. J Hepatol 2016; 65:462-4. [PMID: 27242315 PMCID: PMC5072361 DOI: 10.1016/j.jhep.2016.05.028] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Accepted: 05/20/2016] [Indexed: 12/11/2022]
Affiliation(s)
- Harel Dahari
- The Program for Experimental and Theoretical Modeling, Division of Hepatology, Loyola University Medical Center, Maywood, IL, USA.
| | - Phillippe Halfon
- Internal Medecine and Infectious Disease Hopital Europeen, Laboratoire Alphabio, Marseille, France
| | - Scott J Cotler
- The Program for Experimental and Theoretical Modeling, Division of Hepatology, Loyola University Medical Center, Maywood, IL, USA
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27
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Maasoumy B, Vermehren J, Welker MW, Bremer B, Perner D, Höner Zu Siederdissen C, Deterding K, Lehmann P, Cloherty G, Reinhardt B, Pawlotsky JM, Manns MP, Zeuzem S, Cornberg M, Wedemeyer H, Sarrazin C. Clinical value of on-treatment HCV RNA levels during different sofosbuvir-based antiviral regimens. J Hepatol 2016; 65:473-82. [PMID: 27085252 DOI: 10.1016/j.jhep.2016.04.006] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Revised: 01/08/2016] [Accepted: 04/05/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS The European Association for the Study of the Liver (EASL) guidelines recommend HCV RNA measurements at specific time points during sofosbuvir(SOF)-therapy. However, it remains unclear, how these results should be interpreted. We aimed to analyze whether on-treatment HCV RNA levels predict relapse comparing the CobasAmpliPrep/CobasTaqMan v2.0 (CAP/CTM) and Abbott RealTime HCV (ART) assays. METHODS Samples were collected from 298 patients (HCV genotypes; GT1-5) at weeks (w) 0, 1, 2, 4, 8, 12, 16, 20 and 24 during SOF-based therapy at two university clinics and tested for HCV RNA level by CAP/CTM and ART. Patients were treated with SOF/ribavirin (RBV) 12/24 w (n=99), pegylated-interferon-alfa (PegIFN)/SOF/RBV 12 w (n=51), SOF/simeprevir (SMV)±RBV 12 w (n=69) or SOF/daclatasvir±RBV 12/24 w (n=79). RESULTS HCV RNA levels during the first 4weeks of SOF/RBV therapy were significantly lower in GT3 patients who achieved SVR compared with those who relapsed. All GT3 patients with a week 2 result <45IU/ml by CAP/CTM achieved SVR but only 33% of those with ⩾45IU/ml (p=0.0003). Similar results were documented with ART and 60IU/ml as cut-off (SVR: 100% vs. 29%; p=0.0002). In contrast, HCV RNA levels during early treatment phases were not significantly related to relapse in patients treated with other SOF-based regimens. Residual HCV RNA was frequently detected by ART at later stages of therapy. However, SVR rates remained high in these patients. At the end of SOF/SMV±RBV therapy HCV RNA was detectable with ART in 20% of patients, of whom 92% achieved SVR. CONCLUSIONS HCV RNA levels assessed at week 2 of SOF/RBV therapy can predict relapse in GT3-patients. Detectable HCV RNA results at later stages during SOF-based therapy may occur frequently with the more sensitive ART. However, this should not lead to treatment extension. LAY SUMMARY We analyzed the predictive value of hepatitis C virus (HCV) RNA levels measured at different time points for treatment efficacy. We found that the level of HCV RNA measured at week 2 of antiviral therapy can be used to predict treatment success in patients with HCV genotype 3 infection treated with sofosbuvir and ribavirin but not in patients treated with other sofosbuvir-based regimens. Low level HCV RNA is frequently detected by the RealTime HCV assay during later stages of antiviral therapy. However, this is not associated with reoccurrence of HCV RNA after the end of treatment.
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Affiliation(s)
- Benjamin Maasoumy
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hanover, Germany
| | - Johannes Vermehren
- Department of Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Martin-Walter Welker
- Department of Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Birgit Bremer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hanover, Germany
| | - Dany Perner
- Department of Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany
| | | | - Katja Deterding
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hanover, Germany
| | - Patrick Lehmann
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hanover, Germany
| | | | | | - Jean-Michel Pawlotsky
- National Reference Center for Viral Hepatitis B, C and D, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hanover, Germany
| | - Stefan Zeuzem
- Department of Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hanover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hanover, Germany
| | - Christoph Sarrazin
- Department of Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany.
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Garbuglia AR, Visco-Comandini U, Lionetti R, Lapa D, Castiglione F, D’Offizi G, Taibi C, Montalbano M, Capobianchi MR, Paci P. Ultrasensitive HCV RNA Quantification in Antiviral Triple Therapy: New Insight on Viral Clearance Dynamics and Treatment Outcome Predictors. PLoS One 2016; 11:e0158989. [PMID: 27560794 PMCID: PMC4999094 DOI: 10.1371/journal.pone.0158989] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Accepted: 06/25/2016] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVES Identifying the predictive factors of Sustained Virological Response (SVR) represents an important challenge in new interferon-based DAA therapies. Here, we analyzed the kinetics of antiviral response associated with a triple drug regimen, and the association between negative residual viral load at different time points during treatment. METHODS Twenty-three HCV genotype 1 (GT 1a n = 11; GT1b n = 12) infected patients were included in the study. Linear Discriminant Analysis (LDA) was used to establish possible association between HCV RNA values at days 1 and 4 from start of therapy and SVR. Principal component analysis (PCA) was applied to analyze the correlation between HCV RNA slope and SVR. A ultrasensitive (US) method was established to measure the residual HCV viral load in those samples which resulted "detected <12IU/ml" or undetectable with ABBOTT standard assay, and was retrospectively used on samples collected at different time points to establish its predictive power for SVR. RESULTS According to LDA, there was no association between SVR and viral kinetics neither at time points earlier than 1 week (days 1 and 4) after therapy initiation nor later. The slopes were not relevant for classifying patients as SVR or no-SVR. No significant differences were observed in the median HCV RNA values at T0 among SVR and no-SVR patients. HCV RNA values with US protocol (LOD 1.2 IU/ml) after 1 month of therapy were considered; the area under the ROC curve was 0.70. Overall, PPV and NPV of undetectable HCV RNA with the US method for SVR was 100% and 46.7%, respectively; sensitivity and specificity were 38.4% and 100% respectively. CONCLUSION HCV RNA "not detected" by the US method after 1 month of treatment is predictive of SVR in first generation Protease inhibitor (PI)-based triple therapy. The US method could have clinical utility for advanced monitoring of virological response in new interferon based DAA combination regimens.
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Affiliation(s)
- Anna Rosa Garbuglia
- Laboratory of Virology, “Lazzaro Spallanzani” National Institute for Infectious Diseases, IRCCS, Rome, Italy
- * E-mail:
| | - Ubaldo Visco-Comandini
- Clinical Department, “Lazzaro Spallanzani” National Institute for Infectious Diseases, IRCCS, Rome, Italy
| | - Raffaella Lionetti
- Clinical Department, “Lazzaro Spallanzani” National Institute for Infectious Diseases, IRCCS, Rome, Italy
| | - Daniele Lapa
- Laboratory of Virology, “Lazzaro Spallanzani” National Institute for Infectious Diseases, IRCCS, Rome, Italy
| | | | - Gianpiero D’Offizi
- Clinical Department, “Lazzaro Spallanzani” National Institute for Infectious Diseases, IRCCS, Rome, Italy
| | - Chiara Taibi
- Clinical Department, “Lazzaro Spallanzani” National Institute for Infectious Diseases, IRCCS, Rome, Italy
| | - Marzia Montalbano
- Clinical Department, “Lazzaro Spallanzani” National Institute for Infectious Diseases, IRCCS, Rome, Italy
| | - Maria Rosaria Capobianchi
- Laboratory of Virology, “Lazzaro Spallanzani” National Institute for Infectious Diseases, IRCCS, Rome, Italy
| | - Paola Paci
- Istituto di Analisi dei Sistemi ed Informatica “Antonio Ruberti” (IASI)—CNR, Rome, Italy
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Wiesmann F, Braun P. Significance of HCV RNA monitoring in the era of new potent therapies. Expert Rev Anti Infect Ther 2016; 14:837-44. [PMID: 27424603 DOI: 10.1080/14787210.2016.1214355] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
INTRODUCTION The development and approval of direct-acting-antivirals (DAA) has revolutionized the treatment of hepatitis C within a few years and opened the door to a new era of shorter, well-tolerated but also highly expensive treatment options. AREAS COVERED Nowadays, reductions of viral load below quantification limits may often be achieved within the first weeks of therapy. Viral breakthroughs during treatment are rarely observed and unfavourable viral genotypes or an advanced liver disease do not necessarily lower the prospect of eradication. For this reason, pan-genotypic DAA-only therapies are about to replace interferon/ribavirin-regimens as the standard of care worldwide. Expert commentary: Consequently, it has become essential to reevaluate the utility of HCV RNA quantification in predicting treatment outcomes and to guide clinical decisions. Is there still a need for a close-meshed monitoring or is it reasonable to limit HCV RNA monitoring to baseline and post-treatment results? This review discusses the pro- and contra arguments in this regard.
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Affiliation(s)
- F Wiesmann
- a PZB Aachen , HIV&Hepatitis Research Group , Aachen , Germany
| | - P Braun
- a PZB Aachen , HIV&Hepatitis Research Group , Aachen , Germany
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Dahari H, Canini L, Graw F, Uprichard SL, Araújo ESA, Penaranda G, Coquet E, Chiche L, Riso A, Renou C, Bourliere M, Cotler SJ, Halfon P. HCV kinetic and modeling analyses indicate similar time to cure among sofosbuvir combination regimens with daclatasvir, simeprevir or ledipasvir. J Hepatol 2016; 64:1232-9. [PMID: 26907973 PMCID: PMC5081285 DOI: 10.1016/j.jhep.2016.02.022] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Revised: 12/24/2015] [Accepted: 02/08/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Recent clinical trials of direct-acting-antiviral agents (DAAs) against hepatitis C virus (HCV) achieved >90% sustained virological response (SVR) rates, suggesting that cure often took place before the end of treatment (EOT). We sought to evaluate retrospectively whether early response kinetics can provide the basis to individualize therapy to achieve optimal results while reducing duration and cost. METHODS 58 chronic HCV patients were treated with 12-week sofosbuvir+simeprevir (n=19), sofosbuvir+daclatasvir (n=19), or sofosbuvir+ledipasvir in three French referral centers. HCV was measured at baseline, day 2, every other week, EOT and 12weeks post EOT. Mathematical modeling was used to predict the time to cure, i.e., <1 virus copy in the entire extracellular body fluid. RESULTS All but one patient who relapsed achieved SVR. Mean age was 60±11years, 53% were male, 86% HCV genotype-1, 9% HIV coinfected, 43% advanced fibrosis (F3), and 57% had cirrhosis. At weeks 2, 4 and 6, 48%, 88% and 100% of patients had HCV<15IU/ml, with 27%, 74% and 91% of observations having target not detected, respectively. Modeling results predicted that 23 (43%), 16 (30%), 7 (13%), 5 (9%) and 3 (5%) subjects were predicted to reach cure within 6, 8, 10, 12 and 13weeks of therapy, respectively. The modeling suggested that the patient who relapsed would have benefitted from an additional week of sofosbuvir+ledipasvir. Adjusting duration of treatment according to the modeling predicts reduced medication costs of 43-45% and 17-30% in subjects who had HCV<15IU/ml at weeks 2 and 4, respectively. CONCLUSIONS The use of early viral kinetic analysis has the potential to individualize duration of DAA therapy with a projected average cost saving of 16-20% per 100-treated persons.
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Affiliation(s)
- Harel Dahari
- The Program for Experimental & Theoretical Modeling, Division of Hepatology, Loyola University Medical Center, Maywood, IL, USA; Theoretical Biology & Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM, USA.
| | - Laetitia Canini
- The Program for Experimental & Theoretical Modeling, Division of Hepatology, Loyola University Medical Center, Maywood, IL, USA; Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, United Kingdom
| | - Frederik Graw
- Center for Modeling and Simulation in the Biosciences, BioQuant Center, Heidelberg University, Heidelberg, Germany
| | - Susan L Uprichard
- The Program for Experimental & Theoretical Modeling, Division of Hepatology, Loyola University Medical Center, Maywood, IL, USA
| | | | | | - Emilie Coquet
- Internal Medicine and Infectious Disease, Hôpital Européen, Marseille, France
| | - Laurent Chiche
- Internal Medicine and Infectious Disease, Hôpital Européen, Marseille, France
| | - Aurelie Riso
- Division of Hepatology, Hôpital Saint Joseph, Marseille, France
| | | | - Marc Bourliere
- Division of Hepatology, Hôpital Saint Joseph, Marseille, France
| | - Scott J Cotler
- The Program for Experimental & Theoretical Modeling, Division of Hepatology, Loyola University Medical Center, Maywood, IL, USA
| | - Philippe Halfon
- Laboratoire Alphabio, Marseille, France; Internal Medicine and Infectious Disease, Hôpital Européen, Marseille, France.
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31
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Welzel TM, Reddy KR, Flamm SL, Denning J, Lin M, Hyland R, Pang PS, McHutchison JG, Charlton M, Everson GT, Zeuzem S, Afdhal N. On-treatment HCV RNA in patients with varying degrees of fibrosis and cirrhosis in the SOLAR-1 trial. Antivir Ther 2016; 21:541-546. [PMID: 26891418 DOI: 10.3851/imp3037] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/21/2016] [Indexed: 10/22/2022]
Abstract
BACKGROUND In the Phase II SOLAR-1 study, 12 or 24 weeks of ledipasvir/sofosbuvir and ribavirin yielded high sustained virological response rates at 12 weeks (SVR12) in patients with chronic HCV infection and advanced liver disease, including untransplanted patients with decompensated cirrhosis and liver transplant recipients with all stages of liver disease. METHODS We performed a post hoc analysis using data from this study to investigate associations between baseline characteristics and early on-treatment HCV RNA, and to determine the utility of early virological response (week 2 and 4) to predict SVR12. Serum HCV RNA was quantified using the Roche COBAS® Ampliprep®/Cobas TaqMan HCV Test, Version 2.0 with a lower limit of quantification (LLOQ) of 15 IU/ml. RESULTS Most patients achieved HCV RNA <LLOQ by treatment week 4 and target not detected (TND) by week 6. Baseline factors significantly associated with HCV RNA <LLOQ at week 2 were low HCV RNA (<800,000 IU/ml), absence of cirrhosis, age <60 years and no prior treatment experience. At week 4, low HCV RNA, absence of cirrhosis and IL28B CC were associated with <LLOQ, TND. No baseline factors were associated with week 6 response. There was no association between early on-treatment HCV RNA and SVR12. CONCLUSIONS On-treatment HCV RNA quantification is of limited clinical use in patients with advanced liver disease and/or liver transplantation and does not predict SVR12. ClinicalTrials.gov: NCT01938430.
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Affiliation(s)
- Tania M Welzel
- Department of Medicine, Johann Wolfgang Goethe University Medical Center, Frankfurt am Main, Germany
| | - K Rajender Reddy
- Viral Hepatitis Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
| | - Steven L Flamm
- Division of Gastroenterology and Hepatology, Northwestern Feinberg School of Medicine, Chicago, IL, USA
| | | | - Ming Lin
- Gilead Sciences, Inc., Foster City, CA, USA
| | - Rob Hyland
- Gilead Sciences, Inc., Foster City, CA, USA
| | | | | | - Michael Charlton
- Division of Hepatology and Liver Transplantation, Intermountain Medical Center, Murray, UT, USA
| | - Gregory T Everson
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Colorado Denver, Aurora, CO, USA
| | - Stefan Zeuzem
- Department of Medicine, Johann Wolfgang Goethe University Medical Center, Frankfurt am Main, Germany
| | - Nezam Afdhal
- Department of Hepatology, Beth Israel Deaconess Medical Center, Boston, MA, USA
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32
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Vermehren J, Maasoumy B, Maan R, Cloherty G, Berkowski C, Feld JJ, Cornberg M, Pawlotsky JM, Zeuzem S, Manns MP, Sarrazin C, Wedemeyer H. Applicability of Hepatitis C Virus RNA Viral Load Thresholds for 8-Week Treatments in Patients With Chronic Hepatitis C Virus Genotype 1 Infection. Clin Infect Dis 2016; 62:1228-1234. [PMID: 26908802 DOI: 10.1093/cid/ciw061] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Accepted: 01/31/2016] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Interferon-free treatment of chronic hepatitis C virus (HCV) genotype 1 infection may be shortened to 8 weeks in treatment-naive, noncirrhotic patients with baseline HCV RNA levels of <4 or <6 million (M) IU/mL based on post-hoc analyses of phase 3 trial data. The applicability of these viral load thresholds in clinical practice is unknown. METHODS Pretreatment and on-treatment serum samples (n = 740) from patients with HCV genotype 1 infection were included for HCV RNA analysis with 2 widely used assays, Cobas AmpliPrep/CobasTaqMan (CAP/CTM) and Abbott RealTime HCV (ART) assays. RESULTS HCV RNA levels were significantly higher with CAP/CTM than with ART (overall difference, +0.11 log10 IU/mL; P < .001). In treatment-naive, noncirrhotic patients, discordance rates around the clinical cutoffs at 4M and 6M IU/mL were 23% and 18%, respectively. The mean differences between assays in discordant samples were 0.38 (4M) and 0.41 (6M) log10 IU/mL, respectively. Overall, 87% and 95% of treatment-naive, noncirrhotic patients, respectively, had baseline HCV RNA levels below 4M and 6M IU/mL with ART. These rates were significantly higher than those measured with CAP/CTM (64% and 78%, respectively; P < .001). Finally, discordance rates around the proposed thresholds in 2 consecutive samples of the same patient were in the range of 1%-2% for ART and 13%-17% for CAP/CTM. CONCLUSIONS Selection of patients for 8-week regimens on the basis of a single HCV RNA determination may not be reliable because viral load levels around the proposed clinical thresholds show significant interassay and intrapatient variability.
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Affiliation(s)
| | - Benjamin Maasoumy
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany
| | - Raoel Maan
- Toronto Centre for Liver Disease, Sandra Rotman Centre for Global Health, University of Toronto, Ontario, Canada.,Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, The Netherlands
| | | | | | - Jordan J Feld
- Toronto Centre for Liver Disease, Sandra Rotman Centre for Global Health, University of Toronto, Ontario, Canada
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany
| | - Jean-Michel Pawlotsky
- National Reference Center for Viral Hepatitis B, C and D, Hôpital Henri Mondor, Université Paris-Est.,INSERM U955, Créteil, France
| | - Stefan Zeuzem
- Medizinische Klinik 1, Universitätsklinikum Frankfurt
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany
| | | | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany
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Serfaty L. Follow-up of patients with chronic hepatitis C and a sustained viral response. Liver Int 2016; 36 Suppl 1:67-71. [PMID: 26725900 DOI: 10.1111/liv.13016] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Accepted: 11/03/2015] [Indexed: 12/12/2022]
Abstract
Patients with chronic hepatitis C who achieve a sustained virological response (SVR) after antiviral treatment have improved survival and liver-related morbidity compared to non-SVR patients. However, long-term follow-up studies in SVR patients have shown that the regression of fibrosis varies and the risk of liver-related complications remains, even in the absence of cirrhosis. While patients with cirrhosis are still at risk of hepatocellular carcinoma, comorbidities such as diabetes, obesity or alcohol consumption may play a major role in the outcome of liver disease in SVR patients without cirrhosis. The risk of re-infection is high in patients with a persistent risk of contamination such as IV drug users or men who have sex with men. Thus, in the era of highly efficient DAAs regimens, monitoring after a cure of HCV infection remains a major challenge in SVR patients. This review describes long-term HCV infection and liver-related outcomes in SVR patients, as well as the profile of patients who are still at risk of progression, and monitoring techniques including non-invasive markers for the assessment of fibrosis.
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Affiliation(s)
- Lawrence Serfaty
- AP-HP, Service d'Hépatologie, Hôpital Saint-Antoine, F75012, Paris, France.,UPMC Univ Paris 6, UMR_S938, F75012, Paris, France
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Role of Serologic and Molecular Diagnostic Assays in Identification and Management of Hepatitis C Virus Infection. J Clin Microbiol 2015; 54:265-73. [PMID: 26659219 PMCID: PMC4733206 DOI: 10.1128/jcm.02407-15] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The drugs available for the treatment of hepatitis C virus (HCV) have evolved to provide shorter treatment duration and higher rates of sustained virologic response (SVR), and the role of HCV infection diagnostic tests has had to evolve in order to meet changing clinical needs. This review gives an overview on the role of HCV infection diagnostic testing (molecular and serological tools) used in the diagnosis and management of HCV infection. All of this critical information guides physician decisions to optimize patient clinical outcomes. Also discussed is the future direction of diagnostic testing in the context of further advances in drug development.
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Coppola N, Pisaturo M, Zampino R, Macera M, Sagnelli C, Sagnelli E. Hepatitis C virus markers in infection by hepatitis C virus: In the era of directly acting antivirals. World J Gastroenterol 2015; 21:10749-10759. [PMID: 26478667 PMCID: PMC4600577 DOI: 10.3748/wjg.v21.i38.10749] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2015] [Revised: 07/04/2015] [Accepted: 09/02/2015] [Indexed: 02/06/2023] Open
Abstract
About 130-170 million people are infected with the hepatitis C virus (HCV) worldwide and more than 350000 people die each year of HCV-related liver diseases. The combination of pegylated interferon (Peg-IFN) and ribavirin (RBV) was recommended as the treatment of choice for chronic hepatitis C for nearly a decade. In 2011 the directly acting antivirals (DAA) HCV NS3/4A protease inhibitors, telaprevir and boceprevir, were approved to treat HCV-genotype-1 infection, each in triple combination with Peg-IFN and RBV. These treatments allowed higher rates of SVR than the double Peg-IFN + RBV, but the low tolerability and high pill burden of these triple regimes were responsible for reduced adherence and early treatment discontinuation. The second and third wave DAAs introduced in 2013-2014 enhanced the efficacy and tolerability of anti-HCV treatment. Consequently, the traditional indicators for disease management and predictors of treatment response should be revised in light of these new therapeutic options. This review article will focus on the use of the markers of HCV infection and replication, of laboratory and instrumental data to define the stage of the disease and of predictors, if any, of response to therapy in the DAA era. The article is addressed particularly to physicians who have patients with hepatitis C in care in their everyday clinical practice.
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Ferenci P, Kozbial K, Mandorfer M, Hofer H. HCV targeting of patients with cirrhosis. J Hepatol 2015; 63:1015-1022. [PMID: 26100497 DOI: 10.1016/j.jhep.2015.06.003] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2015] [Revised: 06/09/2015] [Accepted: 06/10/2015] [Indexed: 12/15/2022]
Abstract
Interferon (IFN)-free treatments are now the treatment of choice for patients with chronic hepatitis C. Previously difficult to treat patients by IFN-containing treatments can now be treated safely by IFN-free therapies. More than 90% of hepatitis C genotype 1 and 4 patients with compensated cirrhosis or after orthotopic liver transplantation (OLT) can be cured by sofosbuvir combined with simeprevir, daclatasvir or ledipasvir, or by the paritaprevir/ritona-vir/ombitasvir/±dasabuvir (3D) combination. Addition of ribavirin confers to a minimal, if any, benefit to increase SVR. The need for ribavirin is controversial and remains to be studied. The optimal length of treatment is still unknown, and an individual approach may be needed. Most patients require only 12weeks of therapy. The safety of these drugs is not fully explored in patients with decompensated cirrhosis (Child-Pugh C), who should not be treated with protease inhibitors. In cirrhosis hepatitis C virus eradication does not necessarily mean a cure of the disease and patients regularly require follow-up. Drug-drug interactions with immunosuppressant in patients after OLT are easier to manage but still require attention. Better drugs are needed for genotype 3 patients.
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Affiliation(s)
- Peter Ferenci
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
| | - Karin Kozbial
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Harald Hofer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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Abstract
Mathematically modelling changes in HCV RNA levels measured in patients who receive antiviral therapy has yielded many insights into the pathogenesis and effects of treatment on the virus. By determining how rapidly HCV is cleared when viral replication is interrupted by a therapy, one can deduce how rapidly the virus is produced in patients before treatment. This knowledge, coupled with estimates of the HCV mutation rate, enables one to estimate the frequency with which drug resistant variants arise. Modelling HCV also permits the deduction of the effectiveness of an antiviral agent at blocking HCV replication from the magnitude of the initial viral decline. One can also estimate the lifespan of an HCV-infected cell from the slope of the subsequent viral decline and determine the duration of therapy needed to cure infection. The original understanding of HCV RNA decline under interferon-based therapies obtained by modelling needed to be revised in order to interpret the HCV RNA decline kinetics seen when using direct-acting antiviral agents (DAAs). There also exist unresolved issues involving understanding therapies with combinations of DAAs, such as the presence of detectable HCV RNA at the end of therapy in patients who nonetheless have a sustained virologic response.
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Affiliation(s)
- Alan S Perelson
- Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, Los Alamos, NM 87545, USA
| | - Jeremie Guedj
- INSERM, IAME, UMR 1137, 16 Rue Henri Huchard, F-75018 Paris, France
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Abstract
Interferon-free regimes are now the treatment of choice for patients with chronic hepatitis C; previously patients who were 'difficult-to-treat' using interferon-containing treatments can now safely be treated with such therapies. More than 90% of patients infected with HCV genotype 1 or 4, compensated cirrhosis, or who have had liver transplantation, can be cured with the use of sofosbuvir combined with simeprevir, daclatasvir or ledipasvir, or by the combination of paritaprevir with ritonavir, ombitasvir and with or without dasabuvir. Addition of ribavirin seems to shorten treatment duration. However, the safety of these drugs is not fully explored in patients with decompensated cirrhosis (that is, those with Child-Pugh class C disease), and protease inhibitors should not be used in this group. The optimal use of interferon-free regimes in patients with renal failure or after kidney transplantation is currently being studied. However, new and improved drugs are needed to treat patients infected with HCV genotype 3. Unfortunately, the broad application of new HCV treatments is limited by their high costs. In this Review, I discuss the treatment of patients with hepatitis C with compensated and decompensated cirrhosis, before and after orthotopic liver transplantation and in patients with impaired kidney function.
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Affiliation(s)
- Peter Ferenci
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria
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Liu B, Xiang Y, Zhang HS. Circulating microRNA-196a as a candidate diagnostic biomarker for chronic hepatitis C. Mol Med Rep 2015; 12:105-10. [PMID: 25738504 PMCID: PMC4438874 DOI: 10.3892/mmr.2015.3386] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Accepted: 01/22/2015] [Indexed: 02/07/2023] Open
Abstract
Previous studies have demonstrated the inhibitory effect of microRNA (miR)-196a on hepatitis C virus (HCV) expression in human hepatocytes. However, the clinical implications of aberrant miR-196a expression and the application of circulating miR-196a in the diagnosis and management of chronic hepatitis C (CHC) require further investigation. The present study aimed to examine the possibility of using serum miR-196a as a biomarker for CHC. The Affymetrix miRNA array platform was used for miRNA expression profiling in adenovirus (Ad)-HCV core-infected (HepG2-HCV) and Ad-enhanced green fluorescence protein (EGFP)-infected HepG2 cells (HepG2-control). miR-196a downregulation and levels were analyzed using stem-loop reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis of the sera of 43 patients with CHC and 22 healthy controls. A total of six miRNAs were identified as significantly different (≥1.5 fold; P≤0.05) between the two groups. Of note, significant miR-196a downregulation was observed in HepG2-HCV as compared with HepG2-EGFP. Furthermore, as compared with that of the healthy control group, serum miR-196a was demonstrated to be significantly lower in patients with CHC. In addition, analysis of the receiver operating characteristic (ROC) curve for serum miR-196a revealed an area under the ROC curve of 0.849 (95% confidence interval, 0.756–0.941; P<0.001) with 81.8% sensitivity and 76.7% specificity in discriminating chronic HCV infection from healthy controls at a cut-off value of 6.115×10‒5, demonstrating significant diagnostic value for CHC. However, no correlation was identified between serum miR-196a and alanine aminotransferase, aspartate aminotransferase or HCV-RNA. In conclusion, the present study identified circulating miR-196a as a specific and noninvasive candidate biomarker for the diagnosis of CHC.
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Affiliation(s)
- Bo Liu
- Department of Burns and Plastic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Ying Xiang
- Department of Burns and Plastic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Heng-Shu Zhang
- Department of Burns and Plastic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
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