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In 2016, the Hepatitis B and C Public Policy Association (HepBCPPA), gathered all the main stakeholders in the field of hepatitis C virus (HCV) to launch the now landmark HCV Elimination Manifesto, calling for the elimination of HCV in the EU by 2030. Since then, many European countries have made progress towards HCV elimination. Multiple programmes—from the municipality level to the EU level—were launched, resulting in an overall decrease in viremic HCV infections and liver-related mortality. However, as of 2021, most countries are not on track to reach the 2030 HCV elimination targets set by the WHO. Moreover, the COVID-19 pandemic has resulted in a decrease in HCV diagnoses and fewer direct-acting antiviral treatment initiations in 2020. Diagnostic and therapeutic tools to easily diagnose and treat chronic HCV infection are now well established. Treating all patients with chronic HCV infection is more cost-saving than treating and caring for patients with liver-related complications, decompensated cirrhosis or hepatocellular carcinoma. It is more important than ever to reinforce and scale-up action towards HCV elimination. Yet, efforts urgently need the dedicated commitment of policymakers at all governmental and policy levels. Therefore, the third EU Policy Summit, held in March 2021, featured EU parliamentarians and other key decision makers to promote dialogue and take strides towards securing wider EU commitment to advance and achieve HCV elimination by 2030. We have summarized the key action points and reported the ‘Call-to-Action’ statement supported by all the major relevant European associations in the field.

Description: The Kidney Disease: Improving Global Outcomes (KDIGO) 2022 clinical practice guideline on prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease (CKD) is an update of the 2018 guideline from KDIGO.Methods: The KDIGO Work Group (WG) updated the guideline, which included reviewing and grading new evidence that was identified and summarized. As in the previous guideline, the WG used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to appraise evidence and rate the strength of recommendations and used expert judgment to develop recommendations. New evidence led to updating of recommendations in the chapters on treatment of hepatitis C virus (HCV) infection in patients with CKD (Chapter 2), management of HCV infection before and after kidney transplant (Chapter 4), and diagnosis and management of kidney disease associated with HCV infection (Chapter 5). Recommendations in chapters on detection and evaluation of hepatitis C in CKD (Chapter 1) and prevention of HCV transmission in hemodialysis units (Chapter 3) were not updated because of an absence of significant new evidence.Recommendations: The 2022 updated guideline includes 43 graded recommendations and 20 ungraded recommendations, 7 of which are new or modified on the basis of the most recent evidence and consensus among the WG members. The updated guidelines recommend expanding treatment of hepatitis C with sofosbuvir-based regimens to patients with CKD glomerular filtration rate categories G4 and G5, including those receiving dialysis; expanding the donor pool for kidney transplant recipients by accepting HCV-positive kidneys regardless of the recipient's HCV status; and initiating direct-acting antiviral treatment of HCV-infected patients with clinical evidence of glomerulonephritis without requiring kidney biopsy. The update also addresses the use of immunosuppressive regimens in such patients., Funding Agencies|KDIGO

Infection with the hepatitis C virus (HCV) has adverse liver, kidney, and cardiovascular consequences in patients with chronic kidney disease (CKD), including those on dialysis therapy or with a kidney transplant. Since the publication of the Kidney Disease: Improving Global Outcomes (KDIGO) HCV Guideline in 2018, advances in HCV management, particularly in the field of antiviral therapy and treatment of HCV-associated glomerular diseases, coupled with increased usage of HCV-positive kidney grafts, have prompted a reexamination of the 2018 guideline. As a result, the Work Group performed a comprehensive review and revised the 2018 guidance. This Executive Summary highlights key aspects of the updated guideline recommendations for 3 chapters: Chapter 2: Treatment of HCV infection in patients with CKD; Chapter 4: Management of HCV-infected patients before and after kidney transplantation; and Chapter 5: Diagnosis and management of kidney diseases associated with HCV infection., Funding Agencies|KDIGO

Infection with the hepatitis C virus (HCV) has adverse liver, kidney, and cardiovascular consequences in patients with chronic kidney disease (CKD), including those on dialysis therapy or with a kidney transplant. Since the publication of the Kidney Disease: Improving Global Outcomes (KDIGO) HCV Guideline in 2018, advances in HCV management, particularly in the field of antiviral therapy and treatment of HCV-associated glomerular diseases, coupled with increased usage of HCV-positive kidney grafts, have prompted a reexamination of the 2018 guideline. As a result, the Work Group performed a comprehensive review and revised the 2018 guidance. This Executive Summary highlights key aspects of the updated guideline recommendations for 3 chapters: Chapter 2: Treatment of HCV infection in patients with CKD; Chapter 4: Management of HCV-infected patients before and after kidney transplantation; and Chapter 5: Diagnosis and management of kidney diseases associated with HCV infection., Funding Agencies|KDIGO

Infection with the hepatitis C virus (HCV) has adverse liver, kidney, and cardiovascular consequences in patients with chronic kidney disease (CKD), including those on dialysis therapy or with a kidney transplant. Since the publication of the Kidney Disease: Improving Global Outcomes (KDIGO) HCV Guideline in 2018, advances in HCV management, particularly in the field of antiviral therapy and treatment of HCV-associated glomerular diseases, coupled with increased usage of HCV-positive kidney grafts, have prompted a reexamination of the 2018 guideline. As a result, the Work Group performed a comprehensive review and revised the 2018 guidance. This Executive Summary highlights key aspects of the updated guideline recommendations for 3 chapters: Chapter 2: Treatment of HCV infection in patients with CKD; Chapter 4: Management of HCV-infected patients before and after kidney transplantation; and Chapter 5: Diagnosis and management of kidney diseases associated with HCV infection., Funding Agencies|KDIGO

Infection with the hepatitis C virus (HCV) has adverse liver, kidney, and cardiovascular consequences in patients with chronic kidney disease (CKD), including those on dialysis therapy or with a kidney transplant. Since the publication of the Kidney Disease: Improving Global Outcomes (KDIGO) HCV Guideline in 2018, advances in HCV management, particularly in the field of antiviral therapy and treatment of HCV-associated glomerular diseases, coupled with increased usage of HCV-positive kidney grafts, have prompted a reexamination of the 2018 guideline. As a result, the Work Group performed a comprehensive review and revised the 2018 guidance. This Executive Summary highlights key aspects of the updated guideline recommendations for 3 chapters: Chapter 2: Treatment of HCV infection in patients with CKD; Chapter 4: Management of HCV-infected patients before and after kidney transplantation; and Chapter 5: Diagnosis and management of kidney diseases associated with HCV infection., Funding Agencies|KDIGO

Infection with the hepatitis C virus (HCV) has adverse liver, kidney, and cardiovascular consequences in patients with chronic kidney disease (CKD), including those on dialysis therapy or with a kidney transplant. Since the publication of the Kidney Disease: Improving Global Outcomes (KDIGO) HCV Guideline in 2018, advances in HCV management, particularly in the field of antiviral therapy and treatment of HCV-associated glomerular diseases, coupled with increased usage of HCV-positive kidney grafts, have prompted a reexamination of the 2018 guideline. As a result, the Work Group performed a comprehensive review and revised the 2018 guidance. This Executive Summary highlights key aspects of the updated guideline recommendations for 3 chapters: Chapter 2: Treatment of HCV infection in patients with CKD; Chapter 4: Management of HCV-infected patients before and after kidney transplantation; and Chapter 5: Diagnosis and management of kidney diseases associated with HCV infection., Funding Agencies|KDIGO

Hepatitis C virus (HCV) infection remains commoner in patients with chronic kidney disease (CKD) than the population at large.1 In the haemodialysis (HD) population, HCV infection in part reflects acquisition of infection within dialysis units where its transmission can be effectively prevented by meticulous attention to body fluid precautions.2 A series of studies have confirmed that HCV transmission on HD reflects lack of adherence to these precautions.3 In contrast to the prevention of hepatitis B transmission in this setting, dedicated dialysis machines for HCV-infected patients are not recommended.4 The likelihood of HCV acquisition while on HD is increased in units with a higher background prevalence of HCV infection, so an infected HD patient also places others at risk. [...]

Hepatitis C virus (HCV) infection is more prevalent and is associated with higher mortality in patients receiving dialysis and in kidney transplant recipients than in the general population. Kidney transplant recipients who are HCV-positive are also at higher risk of allograft and liver failure than are HCV-negative recipients. Moreover, HCV infection is associated with a higher incidence and faster progression of diabetes mellitus and chronic kidney disease (CKD), as well as a higher incidence of systemic (especially cardiovascular) complications. The finding that these complications of HCV infection are attenuated in patients who achieve a sustained virologic response (SVR) emphasizes the need to treat patients with CKD who are HCV-positive with oral antiviral therapies. Fortunately, the available evidence suggests that a SVR can be achieved in >95% of patients with late-stage CKD and in kidney transplant recipients. According to international guidelines, all patients with CKD and HCV infection should be considered for treatment with direct acting antivirals (DAAs), prioritizing those with symptomatic cryoglobulinaemic vasculitis, extensive liver fibrosis and stage 4-5 CKD. DAA treatment can be delayed until after transplantation in recipients whose waiting time is markedly reduced by accepting an HCV-positive organ. An emerging issue is the long-term renal safety of DAAs, which requires a re-appraisal. Overall, the elimination of HCV from patients with CKD now seems to be achievable, provided that DAA treatment is coupled with reinforced hygienic precautions to prevent reinfections in dialysis units.

DESCRIPTION: The Kidney Disease: Improving Global Outcomes (KDIGO) 2018 clinical practice guideline for the prevention, diagnosis, evaluation, and treatment of hepatitis C virus (HCV) infection in chronic kidney disease (CKD) is an extensive update of KDIGO's 2008 guideline on HCV infection in CKD. This update reflects the major advances since the introduction of direct-acting antivirals (DAAs) in the management of HCV infection in the CKD population. METHODS: The KDIGO work group tasked with developing the HCV and CKD guideline defined the scope of the guideline, gathered evidence, determined topics for systematic review, and graded the quality of evidence previously summarized by the evidence review team. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach was used to appraise the quality of evidence and rate the strength of the recommendations. Searches of the English-language literature were conducted through May 2017 and were supplemented with targeted searches for studies of DAA treatment and with abstracts from nephrology, hepatology, and transplantation conferences. A review process involving many stakeholders, subject matter experts, and industry and national organizations informed the guideline's final modification. RECOMMENDATION: The updated guideline comprises 66 recommendations. This synopsis focuses on 32 key recommendations pertinent to the prevention, diagnosis, treatment, and management of HCV infection in adult CKD populations.

AGATE-I Part I previously reported high sustained virologic response rates in hepatitis C genotype 4 patients with cirrhosis, with 12 and 16 weeks' treatment with a combination of two direct-acting antivirals, ombitasvir and paritaprevir (codosed with ritonavir), plus ribavirin. Part II, reported here, extended the trial to include a 24-week treatment arm to fully assess treatment duration in patients with chronic hepatitis C genotype 4 infection and compensated cirrhosis. Enrollment took place between June and November of 2015. Treatment-naive and interferon-experienced patients with chronic hepatitis C genotype 4 infection and compensated cirrhosis were enrolled into Arm C; patients previously treated with a sofosbuvir-based regimen were enrolled into Arm D. All patients received a 24-week treatment with ombitasvir, paritaprevir, and ritonavir plus ribavirin. The primary outcome was the proportion of patients with a sustained virologic response (hepatitis C virus RNA < 25 IU/mL) at posttreatment week 12 in the intention-to-treat population. The safety population included all patients who received at least one dose of study drug. In total, 64 patients were enrolled into AGATE-I Part II. Sustained virologic response at posttreatment week 12 was achieved in 57 of 61 patients (93.4%; 97.5% confidence interval, 92.6-97.7) in Arm C and 3 of 3 patients (100%) in Arm D. Two patients were missing SVR12 data, and two prematurely discontinued treatment. The most common adverse events for Arm C were fatigue (16 [26%]) and asthenia (15 [25%]). Results were comparable with those reported in Part I. AGATE-I Part II indicates that extending treatment beyond 12 weeks in genotype 4-infected patients with compensated cirrhosis does not offer additional benefit.

Background and Aims: AGATE-I Part I previously reported high sustained virologic response rates in hepatitis C genotype 4 patients with cirrhosis, with 12 and 16 weeks' treatment with a combination of two direct-acting antivirals, ombitasvir and paritaprevir (codosed with ritonavir), plus ribavirin. Part II, reported here, extended the trial to include a 24-week treatment arm to fully assess treatment duration in patients with chronic hepatitis C genotype 4 infection and compensated cirrhosis. Methods: Enrollment took place between June and November of 2015. Treatment-naive and interferon-experienced patients with chronic hepatitis C genotype 4 infection and compensated cirrhosis were enrolled into Arm C; patients previously treated with a sofosbuvir-based regimen were enrolled into Arm D. All patients received a 24-week treatment with ombitasvir, paritaprevir, and ritonavir plus ribavirin. The primary outcome was the proportion of patients with a sustained virologic response (hepatitis C virus RNA < 25 IU/mL) at posttreatment week 12 in the intention-to-treat population. The safety population included all patients who received at least one dose of study drug. Results: In total, 64 patients were enrolled into AGATE-I Part II. Sustained virologic response at posttreatment week 12 was achieved in 57 of 61 patients (93.4%; 97.5% confidence interval, 92.6-97.7) in Arm C and 3 of 3 patients (100%) in Arm D. Two patients were missing SVR12 data, and two prematurely discontinued treatment. The most common adverse events for Arm C were fatigue (16 [26%]) and asthenia (15 [25%]). Results were comparable with those reported in Part I. Conclusions: AGATE-I Part II indicates that extending treatment beyond 12 weeks in genotype 4–infected patients with compensated cirrhosis does not offer additional benefit., SCOPUS: ar.j, info:eu-repo/semantics/published

Two-dimensional shear wave elastography (2D-SWE) has proven to be efficient for the evaluation of liver fibrosis in small to moderate-sized clinical trials. We aimed at running a larger-scale meta-analysis of individual data. Centers which have worked with Aixplorer ultrasound equipment were contacted to share their data. Retrospective statistical analysis used direct and paired receiver operating characteristic and area under the receiver operating characteristic curve (AUROC) analyses, accounting for random effects. Data on both 2D-SWE and liver biopsy were available for 1,134 patients from 13 sites, as well as on successful transient elastography in 665 patients. Most patients had chronic hepatitis C (n=379), hepatitis B (n=400), or nonalcoholic fatty liver disease (n=156). AUROCs of 2D-SWE in patients with hepatitis C, hepatitis B, and nonalcoholic fatty liver disease were 86.3%, 90.6%, and 85.5% for diagnosing significant fibrosis and 92.9%, 95.5%, and 91.7% for diagnosing cirrhosis, respectively. The AUROC of 2D-SWE was 0.022-0.084 (95% confidence interval) larger than the AUROC of transient elastography for diagnosing significant fibrosis (P=0.001) and 0.003-0.034 for diagnosing cirrhosis (P=0.022) in all patients. This difference was strongest in hepatitis B patients. Conclusion: 2D-SWE has good to excellent performance for the noninvasive staging of liver fibrosis in patients with hepatitis B; further prospective studies are needed for head-to-head comparison between 2D-SWE and other imaging modalities to establish disease-specific appropriate cutoff points for assessment of fibrosis stage. (Hepatology 2018;67:260-272).

Infection with the hepatitis C virus (HCV) has adverse liver, kidney, and cardiovascular consequences in patients with chronic kidney disease (CKD), including those on dialysis therapy and in those with a kidney transplant. Since the publication of the original Kidney Disease: Improving Global Outcomes (KDIGO) HCV Guideline in 2008, major advances in HCV management, particularly with the advent of direct-acting antiviral therapies, have now made the cure of HCV possible in CKD patients. In addition, diagnostic techniques have evolved to enable the noninvasive diagnosis of liver fibrosis. Therefore, the Work Group undertook a comprehensive review and update of the KDIGO HCV in CKD Guideline. This Executive Summary highlights key aspects of the guideline recommendations.

Background & Aims: Glecaprevir plus pibrentasvir (G/P) is a pangenotypic, once-daily, ribavirin-free direct-acting antiviral (DAA) treatment for hepatitis C virus (HCV) infection. In nine phase II or III clinical trials, G/P therapy achieved rates of sustained virologic response 12 weeks after treatment (SVR12) of 93–100% across all six major HCV genotypes (GTs). An integrated efficacy analysis of 8- and 12-week G/P therapy in patients without cirrhosis with HCV GT 1–6 infection was performed. Methods: Data were pooled from nine phase II and III trials including patients with chronic HCV GT 1–6 infection without cirrhosis who received G/P (300 mg/120 mg) for either 8 or 12 weeks. Patients were treatment naïve or treatment experienced with peginterferon, ribavirin, and/or sofosbuvir; all patients infected with HCV GT 3 were treatment naïve. Efficacy was evaluated as the SVR12 rate. Results: The analysis included 2,041 patients without cirrhosis. In the intent-to-treat population, 943/965 patients (98%) achieved SVR12 when treated for eight weeks, and 1,060/1,076 patients (99%) achieved SVR12 when treated for 12 weeks; the difference in rates was not significant (p = 0.2). A subgroup analysis demonstrated SVR12 rates > 95% across baseline factors traditionally associated with lower efficacy. G/P was well tolerated, with one DAA-related serious adverse event (<0.1%); grade 3 laboratory abnormalities were rare. Conclusions: G/P therapy for eight weeks in patients with chronic HCV GT 1–6 infection without cirrhosis achieved an overall SVR12 rate of 98% irrespective of baseline patient or viral characteristics; four additional weeks of treatment did not significantly increase the SVR12 rate, demonstrating that the optimal treatment duration in this population is eight weeks. Lay summary: In this integrated analysis of nine clinical trials, patients with chronic HCV genotype 1–6 infection without cirrhosis were treated for either 8 or 12 weeks with the direct-acting antivi, SCOPUS: ar.j, info:eu-repo/semantics/published

Background & Aims: More than 90% of cases of hepatocellular carcinoma (HCC) occur in patients with cirrhosis, of which alcohol is a major cause. The CIRRAL cohort aimed to assess the burden of complications in patients with alcoholic cirrhosis, particularly the occurrence of HCC. Methods: Patients with biopsy-proven compensated alcoholic cirrhosis were included then prospectively followed. The main endpoint was the incidence of HCC. Secondary outcomes were incidence of hepatic focal lesions, overall survival (OS), liver-related mortality and event-free survival (EFS). Results: From October 2010 to April 2016, 652 patients were included in 22 French and Belgian centers. During follow-up (median 29 months), HCC was diagnosed in 43 patients. With the limitation derived from the uncertainty of consecutive patients’ inclusion and from a sizable proportion of dropouts (153/652), the incidence of HCC was 2.9 per 100 patient-years, and one- and two-year cumulative incidences of 1.8% and 5.2%, respectively. Although HCC fulfilled the Milan criteria in 33 cases (77%), only 24 patients (56%) underwent curative treatment. An explorative prognostic analysis showed that age, male gender, baseline alpha-fetoprotein, bilirubin and prothrombin were significantly associated with the risk of HCC occurrence. Among 73 deaths, 61 had a recorded cause and 27 were directly attributable to liver disease. At two years, OS, EFS and cumulative incidences of liver-related deaths were 93% (95% CI 90.5–95.4), 80.3% (95% CI 76.9–83.9), and 3.2% (95% CI 1.6–4.8) respectively. Conclusion: This large prospective cohort incompletely representative of the whole population with alcoholic cirrhosis showed: a) an annual incidence of HCC of up to 2.9 per 100 patient-years, suggesting that surveillance might be cost effective in these patients; b) a high proportion of HCC detected within the Milan criteria, but only one-half of detected HCC cases were referred for curative treatments; c) a two-year mortalit, SCOPUS: ar.j, info:eu-repo/semantics/published

INTRODUCTION: We present two consensus definitions of advanced and late stage liver disease being used as epidemiological tools. These definitions can be applied to assess the morbidity caused by liver diseases in different health care systems. We focus is on hepatitis B and C virus infections, because effective and well tolerated treatments for both of these infections have greatly improved our ability to successfully treat and prevent advanced and late stage disease, especially if diagnosed early. A consensus definition of late presentation with viral hepatitis is important to create a homogenous, easy-to-use reference for public health authorities in Europe and elsewhere to better assess the clinical situation on a population basis.METHODS: A working group including viral hepatitis experts from the European Association for the Study of the Liver, experts from the HIV in Europe Initiative, and relevant stakeholders including patient advocacy groups, health policy-makers, international health organisations and surveillance experts, met in 2014 and 2015 to develop a draft consensus definition of late presentation with viral hepatitis for medical care. This was refined through subsequent consultations among the group.RESULTS: Two definitions were agreed upon. Presentation with advanced liver disease caused by chronic viral hepatitis for medical care is defined as a patient with chronic hepatitis B and C and significant fibrosis (≥ F3 assessed by either APRI score > 1.5, FIB-4 > 3.25, Fibrotest > 0.59 or alternatively transient elastography (FibroScan) > 9.5 kPa or liver biopsy ≥ METAVIR stage F3) with no previous antiviral treatment. Late stage liver disease caused by chronic viral hepatitis is clinically defined by the presence of decompensated cirrhosis (at least one symptom of the following: jaundice, hepatic encephalopathy, clinically detectable ascites, variceal bleeding) and/or hepatocellular carcinoma.CONCLUSION: These conse

INTRODUCTION: We present two consensus definitions of advanced and late stage liver disease being used as epidemiological tools. These definitions can be applied to assess the morbidity caused by liver diseases in different health care systems. We focus is on hepatitis B and C virus infections, because effective and well tolerated treatments for both of these infections have greatly improved our ability to successfully treat and prevent advanced and late stage disease, especially if diagnosed early. A consensus definition of late presentation with viral hepatitis is important to create a homogenous, easy-to-use reference for public health authorities in Europe and elsewhere to better assess the clinical situation on a population basis.METHODS: A working group including viral hepatitis experts from the European Association for the Study of the Liver, experts from the HIV in Europe Initiative, and relevant stakeholders including patient advocacy groups, health policy-makers, international health organisations and surveillance experts, met in 2014 and 2015 to develop a draft consensus definition of late presentation with viral hepatitis for medical care. This was refined through subsequent consultations among the group.RESULTS: Two definitions were agreed upon. Presentation with advanced liver disease caused by chronic viral hepatitis for medical care is defined as a patient with chronic hepatitis B and C and significant fibrosis (≥ F3 assessed by either APRI score > 1.5, FIB-4 > 3.25, Fibrotest > 0.59 or alternatively transient elastography (FibroScan) > 9.5 kPa or liver biopsy ≥ METAVIR stage F3) with no previous antiviral treatment. Late stage liver disease caused by chronic viral hepatitis is clinically defined by the presence of decompensated cirrhosis (at least one symptom of the following: jaundice, hepatic encephalopathy, clinically detectable ascites, variceal bleeding) and/or hepatocellular carcinoma.CONCLUSION: These conse

BACKGROUND: Chronic hepatitis C virus (HCV) infection is more prevalent among patients who have chronic kidney disease than among those who do not have the disease. Patients with chronic kidney disease who also have HCV infection are at higher risk for progression to end-stage renal disease than those who have chronic kidney disease without HCV infection. Patients with both HCV infection and advanced chronic kidney disease have limited treatment options. METHODS: We conducted a multicenter, open-label, phase 3 trial to evaluate the efficacy and safety of treatment with the combination of the NS3/4A protease inhibitor glecaprevir and the NS5A inhibitor pibrentasvir for 12 weeks in adults who had HCV genotype 1, 2, 3, 4, 5, or 6 infection and also had compensated liver disease (with or without cirrhosis) with severe renal impairment, dependence on dialysis, or both. Patients had stage 4 or 5 chronic kidney disease and either had received no previous treatment for HCV infection or had received previous treatment with interferon or pegylated interferon, ribavirin, sofosbuvir, or a combination of these medications. The primary end point was a sustained virologic response 12 weeks after the end of treatment. RESULTS: Among the 104 patients enrolled in the trial, 52% had genotype 1 infection, 16% had genotype 2 infection, 11% had genotype 3 infection, 19% had genotype 4 infection, and 2% had genotype 5 or 6 infection. The sustained virologic response rate was 98% (102 of 104 patients; 95% confidence interval, 95 to 100). No patients had virologic failure during treatment, and no patients had a virologic relapse after the end of treatment. Adverse events that were reported in at least 10% of the patients were pruritus, fatigue, and nausea. Serious adverse events were reported in 24% of the patients. Four patients discontinued the trial treatment prematurely because of adverse events; three of these patients had a sustained virologic response. CONCLUSIONS: Treatment with gle, SCOPUS: ar.j, info:eu-repo/semantics/published

Christoph Sarrazin,1 Francesco Castelli,2 Pietro Andreone,3 Maria Buti,4 Massimo Colombo,5 Stanislas Pol,6 Filipe Calinas,7 Massimo Puoti,8 Antonio Olveira,9 Mitchell Shiffman,10 Jerry O Stern,11 George Kukolj,12 Michael Roehrle,13 Stella Aslanyan,11 Qiqi Deng,11 Richard Vinisko,11 Federico J Mensa,11 David R Nelson,14 on behalf of the HCVerso1 and 2 study groups 1Department of Internal Medicine 1, JW Goethe University Hospital, Frankfurt, Germany; 2Department of Infectious and Tropical Diseases, University of Brescia, Brescia, 3Department of Medical and Surgical Sciences, Università di Bologna and Azienda Ospedaliero-Universitaria, Policlinico Sant‘Orsola-Malpighi, Bologna, Italy; 4Department of Internal Medicine, Hospital Universitari Vall d’Hebron and CIBERehd del Instituto Carlos III, Barcelona, Spain; 5Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy; 6University Paris Descartes, Department of Hepatology, Hospital Cochin, APHP and INSERM UMS-20, Institut Pasteur, Paris, France; 7Department of Gastroenterology, Centro Hospitalar de Lisboa Central, Lisbon, Portugal; 8Department of Infectious Diseases, AO Ospedale Niguarda Cà Granda, Milan, Italy; 9Liver Unit, Hospital Universitario La Paz, CIBERehd, Madrid, Spain; 10Liver Institute of Virginia, Bon Secours Health System, Richmond, VA, USA; 11Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA; 12Boehringer Ingelheim Ltd/Ltée, Burlington, ON, Canada; 13Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; 14Clinical and Translational Science Institute, University of Florida, Gainesville, FL, USA Abstract: The interferon-free combination of once-daily faldaprevir 120 mg, twice-daily deleobuvir 600 mg, and weight-based ribavirin was evaluated in two Phase III studies (HCVerso1, HCVerso2) in hepatitis C virus genotype-1b-infected, treatment-naïve patients, including those ineligible for peginterfer

Christoph Sarrazin,1 Francesco Castelli,2 Pietro Andreone,3 Maria Buti,4 Massimo Colombo,5 Stanislas Pol,6 Filipe Calinas,7 Massimo Puoti,8 Antonio Olveira,9 Mitchell Shiffman,10 Jerry O Stern,11 George Kukolj,12 Michael Roehrle,13 Stella Aslanyan,11 Qiqi Deng,11 Richard Vinisko,11 Federico J Mensa,11 David R Nelson,14 on behalf of the HCVerso1 and 2 study groups 1Department of Internal Medicine 1, JW Goethe University Hospital, Frankfurt, Germany; 2Department of Infectious and Tropical Diseases, University of Brescia, Brescia, 3Department of Medical and Surgical Sciences, Università di Bologna and Azienda Ospedaliero-Universitaria, Policlinico Sant‘Orsola-Malpighi, Bologna, Italy; 4Department of Internal Medicine, Hospital Universitari Vall d’Hebron and CIBERehd del Instituto Carlos III, Barcelona, Spain; 5Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy; 6University Paris Descartes, Department of Hepatology, Hospital Cochin, APHP and INSERM UMS-20, Institut Pasteur, Paris, France; 7Department of Gastroenterology, Centro Hospitalar de Lisboa Central, Lisbon, Portugal; 8Department of Infectious Diseases, AO Ospedale Niguarda Cà Granda, Milan, Italy; 9Liver Unit, Hospital Universitario La Paz, CIBERehd, Madrid, Spain; 10Liver Institute of Virginia, Bon Secours Health System, Richmond, VA, USA; 11Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA; 12Boehringer Ingelheim Ltd/Ltée, Burlington, ON, Canada; 13Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; 14Clinical and Translational Science Institute, University of Florida, Gainesville, FL, USA Abstract: The interferon-free combination of once-daily faldaprevir 120 mg, twice-daily deleobuvir 600 mg, and weight-based ribavirin was evaluated in two Phase III studies (HCVerso1, HCVerso2) in hepatitis C virus genotyp

Stanislas Pol, Marion Corouge, Anaïs Vallet-Pichard Université Paris Descartes, Liver Department, Assistance Publique Hôpitaux de Paris, Cochin Hospital, French Institute of Health and Medical Research UMS20, Institut Pasteur, Paris, France Abstract: The treatment of hepatitis C virus has changed dramatically with the rapid advent of numerous new antiviral agents, including direct-acting antivirals and agents with non-viral targets (cyclophilin inhibitors, interferon-lambda, vaccine therapy). Given the better safety profile and high antiviral potency of direct-acting antivirals, their combination in interferon-free oral regimens is becoming the standard of care for hepatitis C virus infection, tailored to individual patients according to the degree of disease progression (fibrosis), hepatitis C virus genotype and subtype, resistance profile, and prior therapeutic history. Results from clinical studies as well as preliminary real-life data regarding the combination of sofosbuvir (a nucleotide polymerase inhibitor) and daclatasvir, a first-in-class NS5A replication complex inhibitor, demonstrate that it is one of the most promising antiviral therapies, with once-daily oral dosing, a low pill burden, good tolerability, and limited drug–drug interactions, in addition to high antiviral potency, with >90% sustained virologic response rates. This combination has high pangenotypic antiviral potency regardless of the severity and patient characteristics. The combination of sofosbuvir and an NS5A inhibitor with ribavirin for 12 weeks appears to be a very good further treatment option in both cirrhotic and treatment-experienced patients whatever the stage of fibrosis. Keywords: hepatitis C virus, direct-acting antivirals, sofosbuvir, daclatasvir

Chronic HCV infections represent a major worldwide public health problem and are responsible for a large proportion of liver related deaths, mostly because of HCV-associated hepatocellular carcinoma and cirrhosis. The treatment of HCV has undergone a rapid and spectacular revolution. In the past 5 years, the launch of direct acting antiviral drugs has seen sustained virological response rates reach 90% and above for many patient groups. The new treatments are effective, well tolerated, allow for shorter treatment regimens and offer new opportunities for previously excluded groups. This therapeutic revolution has changed the rules for treatment of HCV, moving the field towards an interferon-free era and raising the prospect of HCV eradication. This manuscript addresses the new challenges regarding treatment optimisation in the real world, improvement of antiviral efficacy in 'hard-to-treat' groups, the management of patients whose direct acting antiviral drug treatment was unsuccessful, and access to diagnosis and treatment in different parts of the world.

BACKGROUND & AIMS: Twenty-four weeks of treatment with peginterferon and ribavirin for chronic hepatitis C virus (HCV) genotype 2 or 3 infection produces a sustained virologic response (SVR) in 70%-80% of patients. We performed a randomized, double-blind, phase 2b study to assess whether adding daclatasvir, a nonstructural protein 5A (NS5A) inhibitor that is active against these genotypes, improves efficacy and shortens therapy.METHODS: Patients with HCV genotype 2 or 3 infection (n = 151), enrolled at research centers in North America, Europe, or Australia, were assigned randomly to groups given 12 or 16 weeks of daclatasvir (60 mg once daily), or 24 weeks of placebo, each combined with peginterferon alfa-2a and ribavirin. Treatment was extended to 24 weeks for recipients of daclatasvir who did not meet the criteria for early virologic response. The primary end point was SVR at 24 weeks after treatment (SVR24).RESULTS: Baseline characteristics were similar among patients within each HCV genotype group. However, the 80 patients with HCV genotype 3, compared with the 71 patients with HCV genotype 2, were younger (mean age, 45 vs 53 y, respectively), and a larger proportion had cirrhosis (23% vs 1%, respectively). Among patients with HCV genotype 2 infection, an SVR24 was achieved by 83%, 83%, and 63% of those in the daclatasvir 12-week group, the daclatasvir 16-week group, or the placebo group, respectively; among patients with HCV genotype 3 infection, an SVR24 was achieved by 69%, 67%, and 59% of patients in these groups, respectively. Differences between genotypes largely were attributable to the higher frequency of post-treatment relapse among patients infected with HCV genotype 3. In both daclatasvir arms for both HCV genotypes, the lower bound of the 80% confidence interval of the difference in SVR24 rates between the daclatasvir and placebo arms was above -20%, establishing noninferiority. Safety findings were similar among groups, and wer

BACKGROUND: Both hepatitis C virus (HCV) mono-infected and HIV/HCV co-infected patients are in need of safe, effective, all-oral HCV regimens. In a phase 2 study we aimed to assess the efficacy and safety of grazoprevir (MK-5172; HCV NS3/4A protease inhibitor) and two doses of elbasvir (MK-8742; HCV NS5A inhibitor) in patients with HCV mono-infection and HIV/HCV co-infection.METHODS: The C-WORTHY study is a phase 2, multicentre, randomised controlled trial of grazoprevir plus elbasvir with or without ribavirin in patients with HCV; here, we report findings for previously untreated (genotype 1) patients without cirrhosis who were HCV mono-infected or HIV/HCV co-infected. Eligible patients were previously untreated adults aged 18 years or older with chronic HCV genoype 1 infection and HCV RNA at least 10 000 IU/mL in peripheral blood without evidence of cirrhosis, hepatocellular carcinoma, or decompensated liver disease. In part A of the study we randomly assigned HCV-mono-infected patients to receive 12 weeks of grazoprevir (100 mg) plus elbasvir (20 mg or 50 mg) with or without ribavirin (arms A1-3); in part B we assigned HCV-mono-infected patients to 8 or 12 weeks of grazoprevir (100 mg) plus elbasvir (50 mg) with or without ribavirin (arms B1-3) and HIV/HCV co-infected patients to 12 weeks of therapy with or without ribavirin. The primary endpoint was the proportion of patients achieving HCV RNA less than 25 IU/mL 12 weeks after end of treatment (SVR12). Randomisation was by presence or absence of ribavirin, 8 or 12 weeks of treatment, and dosage of elbasvir. Patients were stratified by gentoype 1a versus 1b. The patients, investigators, and study site personnel were masked to treatment group assignements but the funder was not. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT01717326.FINDINGS: 218 patients with HCV mono-infection (n=159) and HIV/HCV co-infection (n=59) were enrolled. SVR12 for patient

OBJECTIVE: To evaluate the safety and efficacy of daclatasvir, an HCV NS5A inhibitor with pangenotypic activity, administered with peginterferon-alfa-2a/ribavirin.DESIGN: In this Phase 2b double-blind, placebo-controlled study, treatment-naive adults with HCV genotype 1 (N=365) or 4 (N=30) infection were randomly assigned (2:2:1) to daclatasvir 20 mg or 60 mg, or placebo once daily plus weekly peginterferon-alfa-2a and twice-daily ribavirin. Daclatasvir recipients achieving protocol-defined response (PDR; HCV-RNA

Up to 60% of patients with hepatitis C virus (HCV) genotype 1 infection do not have a sustained virologic response to therapy with peginterferon alfa plus ribavirin.

Up to 60% of patients with hepatitis C virus (HCV) genotype 1 infection do not have a sustained virologic response to therapy with peginterferon alfa plus ribavirin., Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Up to 60% of patients with hepatitis C virus (HCV) genotype 1 infection do not have a sustained virologic response to therapy with peginterferon alfa plus ribavirin., Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Objective: Recently approved direct acting antivirals provide transformative therapies for chronic hepatitis C virus (HCV) infection. The major clinical challenge remains to identify the undiagnosed patients worldwide, many of whom live in low-income and middle-income countries, where access to nucleic acid testing remains limited. The aim of this study was to develop and validate a point-of-care (PoC) assay for the qualitative detection of HCV RNA. Design: We developed a PoC assay for the qualitative detection of HCV RNA on the PCR Genedrive instrument. We validated the Genedrive HCV assay through a case–control study comparing results with those obtained with the Abbott RealTime HCV test. Results: The PoC assay identified all major HCV genotypes, with a limit of detection of 2362 IU/mL (95% CI 1966 to 2788). Using 422 patients chronically infected with HCV and 503 controls negative for anti-HCV and HCV RNA, the Genedrive HCV assay showed 98.6% sensitivity (95% CI 96.9% to 99.5%) and 100% specificity (95% CI 99.3% to 100%) to detect HCV. In addition, melting peak ratiometric analysis demonstrated proof-of-principle for semiquantification of HCV. The test was further validated in a real clinical setting in a resource-limited country. Conclusion: We report a rapid, simple, portable and accurate PoC molecular test for HCV, with sensitivity and specificity that fulfils the recent FIND/WHO Target Product Profile for HCV decentralised testing in low-income and middle-income countries. This Genedrive HCV assay may positively impact the continuum of HCV care from screening to cure by supporting real-time treatment decisions.

Objective: Recently approved direct acting antivirals provide transformative therapies for chronic hepatitis C virus (HCV) infection. The major clinical challenge remains to identify the undiagnosed patients worldwide, many of whom live in low-income and middle-income countries, where access to nucleic acid testing remains limited. The aim of this study was to develop and validate a point-of-care (PoC) assay for the qualitative detection of HCV RNA. Design: We developed a PoC assay for the qualitative detection of HCV RNA on the PCR Genedrive instrument. We validated the Genedrive HCV assay through a case–control study comparing results with those obtained with the Abbott RealTime HCV test. Results: The PoC assay identified all major HCV genotypes, with a limit of detection of 2362 IU/mL (95% CI 1966 to 2788). Using 422 patients chronically infected with HCV and 503 controls negative for anti-HCV and HCV RNA, the Genedrive HCV assay showed 98.6% sensitivity (95% CI 96.9% to 99.5%) and 100% specificity (95% CI 99.3% to 100%) to detect HCV. In addition, melting peak ratiometric analysis demonstrated proof-of-principle for semiquantification of HCV. The test was further validated in a real clinical setting in a resource-limited country. Conclusion: We report a rapid, simple, portable and accurate PoC molecular test for HCV, with sensitivity and specificity that fulfils the recent FIND/WHO Target Product Profile for HCV decentralised testing in low-income and middle-income countries. This Genedrive HCV assay may positively impact the continuum of HCV care from screening to cure by supporting real-time treatment decisions.

Objective: Recently approved direct acting antivirals provide transformative therapies for chronic hepatitis C virus (HCV) infection. The major clinical challenge remains to identify the undiagnosed patients worldwide, many of whom live in low-income and middle-income countries, where access to nucleic acid testing remains limited. The aim of this study was to develop and validate a point-of-care (PoC) assay for the qualitative detection of HCV RNA. Design: We developed a PoC assay for the qualitative detection of HCV RNA on the PCR Genedrive instrument. We validated the Genedrive HCV assay through a case–control study comparing results with those obtained with the Abbott RealTime HCV test. Results: The PoC assay identified all major HCV genotypes, with a limit of detection of 2362 IU/mL (95% CI 1966 to 2788). Using 422 patients chronically infected with HCV and 503 controls negative for anti-HCV and HCV RNA, the Genedrive HCV assay showed 98.6% sensitivity (95% CI 96.9% to 99.5%) and 100% specificity (95% CI 99.3% to 100%) to detect HCV. In addition, melting peak ratiometric analysis demonstrated proof-of-principle for semiquantification of HCV. The test was further validated in a real clinical setting in a resource-limited country. Conclusion: We report a rapid, simple, portable and accurate PoC molecular test for HCV, with sensitivity and specificity that fulfils the recent FIND/WHO Target Product Profile for HCV decentralised testing in low-income and middle-income countries. This Genedrive HCV assay may positively impact the continuum of HCV care from screening to cure by supporting real-time treatment decisions.

Objective: Recently approved direct acting antivirals provide transformative therapies for chronic hepatitis C virus (HCV) infection. The major clinical challenge remains to identify the undiagnosed patients worldwide, many of whom live in low-income and middle-income countries, where access to nucleic acid testing remains limited. The aim of this study was to develop and validate a point-of-care (PoC) assay for the qualitative detection of HCV RNA. Design: We developed a PoC assay for the qualitative detection of HCV RNA on the PCR Genedrive instrument. We validated the Genedrive HCV assay through a case–control study comparing results with those obtained with the Abbott RealTime HCV test. Results: The PoC assay identified all major HCV genotypes, with a limit of detection of 2362 IU/mL (95% CI 1966 to 2788). Using 422 patients chronically infected with HCV and 503 controls negative for anti-HCV and HCV RNA, the Genedrive HCV assay showed 98.6% sensitivity (95% CI 96.9% to 99.5%) and 100% specificity (95% CI 99.3% to 100%) to detect HCV. In addition, melting peak ratiometric analysis demonstrated proof-of-principle for semiquantification of HCV. The test was further validated in a real clinical setting in a resource-limited country. Conclusion: We report a rapid, simple, portable and accurate PoC molecular test for HCV, with sensitivity and specificity that fulfils the recent FIND/WHO Target Product Profile for HCV decentralised testing in low-income and middle-income countries. This Genedrive HCV assay may positively impact the continuum of HCV care from screening to cure by supporting real-time treatment decisions.

Objective: Recently approved direct acting antivirals provide transformative therapies for chronic hepatitis C virus (HCV) infection. The major clinical challenge remains to identify the undiagnosed patients worldwide, many of whom live in low-income and middle-income countries, where access to nucleic acid testing remains limited. The aim of this study was to develop and validate a point-of-care (PoC) assay for the qualitative detection of HCV RNA. Design: We developed a PoC assay for the qualitative detection of HCV RNA on the PCR Genedrive instrument. We validated the Genedrive HCV assay through a case–control study comparing results with those obtained with the Abbott RealTime HCV test. Results: The PoC assay identified all major HCV genotypes, with a limit of detection of 2362 IU/mL (95% CI 1966 to 2788). Using 422 patients chronically infected with HCV and 503 controls negative for anti-HCV and HCV RNA, the Genedrive HCV assay showed 98.6% sensitivity (95% CI 96.9% to 99.5%) and 100% specificity (95% CI 99.3% to 100%) to detect HCV. In addition, melting peak ratiometric analysis demonstrated proof-of-principle for semiquantification of HCV. The test was further validated in a real clinical setting in a resource-limited country. Conclusion: We report a rapid, simple, portable and accurate PoC molecular test for HCV, with sensitivity and specificity that fulfils the recent FIND/WHO Target Product Profile for HCV decentralised testing in low-income and middle-income countries. This Genedrive HCV assay may positively impact the continuum of HCV care from screening to cure by supporting real-time treatment decisions.