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AbstractIntroductionThe introduction of drugs targeting the virus replication cycle has revolutionized treatment of chronic hepatitis C virus. These drugs, called direct‐acting antivirals, have brought about extremely high rates of virological cure and have increased the number of patients who can receive treatment due to the lack of absolute contraindications. A combination of different classes of direct‐acting antivirals is the current standard of care. Although treatment administration and monitoring has been simplified in recent years, it is still relatively complex and mostly in the hands of specialists. Several factors must be assessed before starting treatment to maximize efficacy and minimize side effects of treatment. In this review, we describe the factors that impact on the efficacy and safety of antiviral treatment for hepatitis C and provide clear recommendations for clinicians prescribing direct‐acting antivirals.MethodsWe reviewed literature to define best practice, based on factors associated with treatment efficacy and safety data to recommend treatment options, baseline and on‐treatment assessments. The review included searches in PubMed, and the abstracts presented at the International Liver Congress TM and The Liver Meeting TM between January 2013 and September 2017.ResultsClinical features that must be assessed before starting treatment include virological factors, such as hepatitis C virus genotype, HIV and hepatitis B coinfection and host factors, such as concomitant medications, liver disease stage and renal function.ConclusionsPatients who start antiviral treatment for chronic hepatitis C require a thorough clinical evaluation. There is a need for assessing factors that impact on the treatment schedule and duration or affect the pharmacokinetics of direct‐acting antivirals.

AbstractBackgroundDirect acting antivirals (DAAs) have revolutionized hepatitis C (HCV) treatment with >90% cure rates even in real‐world studies, giving hope that HCV can be eliminated. However, for DAAs to have a population‐level impact on the burden of HCV disease, treatment uptake needs to be expanded. We investigated temporal trends in HCV treatment uptake and evaluated factors associated with second‐generation DAA initiation and efficacy among key HIV‐HCV co‐infected populations in Canada.MethodsThe Canadian HIV‐HCV Co‐Infection Cohort Study prospectively follows 1699 participants from 18 centres. Among HCV RNA+ participants, we determined the incidence of HCV treatment initiation per year overall and by key populations between 2007 and 2015. Key populations were based on World Health Organization (WHO) guidelines including: people who actively inject drugs (PWID) (reporting injection drug use, last 6 months); Indigenous people; women and men who have sex with men (MSM). Multivariate Cox models were used to estimate adjusted hazard ratios (aHR) and 2‐year probability of initiating second‐generation DAAs for each of the key populations.ResultsOverall, HCV treatment initiation rates increased from 8 (95% CI, 6–11) /100 person‐years in 2013 to 28 (95% CI, 23–33) /100 person‐years in 2015. Among 911 HCV RNA + participants, there were 202 second‐generation DAA initiations (93% with interferon‐free regimens). After adjustment (aHR, 95% CI), active PWID (0.60, 0.38–0.94 compared to people not injecting drugs) and more generally, people with lower income (<$18 000 CAD/year) (0.50, 0.35, 0.71) were less likely to initiate treatment. Conversely, MSM were more likely to initiate 1.95 (1.33, 2.86) compared to heterosexual men. In our cohort, the population profile with the lowest 2‐year probability of initiating DAAs was Indigenous, women who inject drugs (5%, 95% CI 3–8%). Not having any of these risk factors resulted in a 35% (95% CI 32–38%) probability of initiating DAA treatment. Sustained virologic response (SVR) rates were >82% in all key populations.ConclusionWhile treatment uptake has increased with the availability of second‐generation DAAs, marginalized populations, already engaged in care, are still failing to access treatment. Targeted strategies to address barriers are needed to avoid further health inequities and to maximize the public health impact of DAAs.

All-oral direct-acting antiviral drugs (DAAs) for hepatitis C virus, which have response rates of 95% or more, represent a major clinical advance. However, the high list price of DAAs has led many governments to restrict their reimbursement. We reviewed the availability of, and national criteria for, interferon-free DAA reimbursement among countries in the European Union and European Economic Area, and Switzerland. Reimbursement documentation was reviewed between Nov 18, 2016, and Aug 1, 2017. Primary outcomes were fibrosis stage, drug or alcohol use, prescriber type, and HIV co-infection restrictions. Among the 35 European countries and jurisdictions included, the most commonly reimbursed DAA was ombitasvir, paritaprevir, and ritonavir, with dasabuvir, and with or without ribavirin (33 [94%] countries and jurisdictions). 16 (46%) countries and jurisdictions required patients to have fibrosis at stage F2 or higher, 29 (83%) had no listed restrictions based on drug or alcohol use, 33 (94%) required a specialist prescriber, and 34 (97%) had no additional restrictions for people co-infected with HIV and hepatitis C virus. These findings have implications for meeting WHO targets, with evidence of some countries not following the 2016 hepatitis C virus treatment guidelines by the European Association for the Study of Liver.

Lu-Hua Gao, Qing-He Nie, Xi-Tai Zhao Center of Infectious Diseases, Second Affiliated Hospital, Air-Force Military Medical University, Xi'an 710038, People's Republic of ChinaCorrespondence: Qing-He NieCenter of Infectious Diseases, Second Affiliated Hospital, Air-Force Military Medical University, 569 Xinsi Road, Baqiao District, Xi'an 710038, People's Republic of ChinaEmail nhqxan2020@163.comAbstract: Hepatitis C is a major health problem worldwide, frequently resulting in cirrhosis and increasing the risk of hepatocellular carcinoma significantly. In recent years, the advent of direct-acting antivirals (DAAs) has dramatically improved the therapeutic outcomes in hepatitis C patients. In the last two years, several new DAA combinations have been approved for the treatment of the hepatitis C virus (HCV) infection, including elbasvir/grazoprevir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, and glecaprevir/pibrentasvir. The newly approved DAA regimens may be prescribed with other drugs simultaneously, increasing the potential of pharmacokinetic interactions. Therefore, the knowledge and management of drug–drug interactions (DDIs) with DAAs should be considered a key issue in HCV therapy. This review summarizes researches of DDIs focusing on newly approved DAAs (elbasvir, grazoprevir, velpatasvir, voxilaprevir, glecaprevir, pibrentasvir) for patients undergoing HCV treatment to provide clinical consideration for comedication. With respect to DDIs, newly approved DAA regimens, including elbasvir/grazoprevir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, and glecaprevir/pibrentasvir, are safely applicable.Keywords: drug–drug interaction, direct-acting antiviral, chronic hepatitis C, pharmacokinetic, comedication

Background and objectives: this study assessed variations in the blood parameters of patients with hematological disorders infected with HCV throughout a 12-week interferon-free treatment regimen. Materials and methods: We followed a total of 344 patients suffering from chronic hepatitis C, infected with the 1b genotype and concomitant hematological disorders, who benefited from the direct-acting antiviral (DAA) therapy in our clinic. Seven of the most routinely checked blood parameters were analyzed, namely, hemoglobin, leucocyte count, neutrophils, erythrocyte count, platelet count, ALT, and total bilirubin level. In total, 129 patients received a treatment scheme comprising ombitasvir, paritaprevir, ritonavir, and dasabuvir, while the 215 other patients received a sofosbuvir and ledipasvir regimen. Results: Patients enrolled in the study showed remarkably increased ALT levels in the first four weeks of DAA treatment, normalizing to levels below 40 U/L by the end of regimen. There were no other blood parameters that worsened throughout the 12-week regimen to levels below our laboratory's normal range. After 12 weeks of DAA therapy, 309 patients (90%) achieved SVR. Conclusions: Our findings are consistent in evaluating the efficacy and tolerability of direct-acting antivirals for 1b genotype HCV infected patients with associated hematological malignancies under remission, and other hematological disturbances, that were previously unsuccessfully treated with a pegylated interferon regimen. Thus, paving a pathway for government-funded programs being implemented in this direction.

All-oral direct-acting antiviral drugs (DAAs) for hepatitis C virus, which have response rates of 95% or more, represent a major clinical advance. However, the high list price of DAAs has led many governments to restrict their reimbursement. We reviewed the availability of, and national criteria for, interferon-free DAA reimbursement among countries in the European Union and European Economic Area, and Switzerland. Reimbursement documentation was reviewed between Nov 18, 2016, and Aug 1, 2017. Primary outcomes were fibrosis stage, drug or alcohol use, prescriber type, and HIV co-infection restrictions. Among the 35 European countries and jurisdictions included, the most commonly reimbursed DAA was ombitasvir, paritaprevir, and ritonavir, with dasabuvir, and with or without ribavirin (33 [94%] countries and jurisdictions). 16 (46%) countries and jurisdictions required patients to have fibrosis at stage F2 or higher, 29 (83%) had no listed restrictions based on drug or alcohol use, 33 (94%) required a specialist prescriber, and 34 (97%) had no additional restrictions for people co-infected with HIV and hepatitis C virus. These findings have implications for meeting WHO targets, with evidence of some countries not following the 2016 hepatitis C virus treatment guidelines by the European Association for the Study of Liver.

All-oral direct-acting antiviral drugs (DAAs) for hepatitis C virus, which have response rates of 95% or more, represent a major clinical advance. However, the high list price of DAAs has led many governments to restrict their reimbursement. We reviewed the availability of, and national criteria for, interferon-free DAA reimbursement among countries in the European Union and European Economic Area, and Switzerland. Reimbursement documentation was reviewed between Nov 18, 2016, and Aug 1, 2017. Primary outcomes were fibrosis stage, drug or alcohol use, prescriber type, and HIV co-infection restrictions. Among the 35 European countries and jurisdictions included, the most commonly reimbursed DAA was ombitasvir, paritaprevir, and ritonavir, with dasabuvir, and with or without ribavirin (33 [94%] countries and jurisdictions). 16 (46%) countries and jurisdictions required patients to have fibrosis at stage F2 or higher, 29 (83%) had no listed restrictions based on drug or alcohol use, 33 (94%) required a specialist prescriber, and 34 (97%) had no additional restrictions for people co-infected with HIV and hepatitis C virus. These findings have implications for meeting WHO targets, with evidence of some countries not following the 2016 hepatitis C virus treatment guidelines by the European Association for the Study of Liver.

Background and objectives: this study assessed variations in the blood parameters of patients with hematological disorders infected with HCV throughout a 12-week interferon-free treatment regimen. Materials and methods: We followed a total of 344 patients suffering from chronic hepatitis C, infected with the 1b genotype and concomitant hematological disorders, who benefited from the direct-acting antiviral (DAA) therapy in our clinic. Seven of the most routinely checked blood parameters were analyzed, namely, hemoglobin, leucocyte count, neutrophils, erythrocyte count, platelet count, ALT, and total bilirubin level. In total, 129 patients received a treatment scheme comprising ombitasvir, paritaprevir, ritonavir, and dasabuvir, while the 215 other patients received a sofosbuvir and ledipasvir regimen. Results: Patients enrolled in the study showed remarkably increased ALT levels in the first four weeks of DAA treatment, normalizing to levels below 40 U/L by the end of regimen. There were no other blood parameters that worsened throughout the 12-week regimen to levels below our laboratory's normal range. After 12 weeks of DAA therapy, 309 patients (90%) achieved SVR. Conclusions: Our findings are consistent in evaluating the efficacy and tolerability of direct-acting antivirals for 1b genotype HCV infected patients with associated hematological malignancies under remission, and other hematological disturbances, that were previously unsuccessfully treated with a pegylated interferon regimen. Thus, paving a pathway for government-funded programs being implemented in this direction.

Introduction: Hepatitis C virus (HCV), the leading cause of advanced liver disease, has enormous economic burden. Identification of patients at risk of treatment failure could lead to interventions that improve cure rates. Objectives: Our goal was to develop and evaluate a prediction model for HCV treatment failure. Methods: We analyzed HCV patients initiating direct-acting antiviral therapy at four United States institutions. Treatment failure was determined by lack of sustained virologic response (SVR) 12 weeks after treatment completion. From 20 patient-level variables collected before treatment initiation, we identified a subset associated with treatment failure in bivariate analyses. In a derivation set, separate predictive models were developed from 100 bootstrap samples using logistic regression. From the 100 models, variables were ranked by frequency of selection as predictors to create four final candidate models, using cutoffs of ≥80%, ≥50%, ≥40%, and all variables. In a validation set, predictive performance was compared across models using area under the receiver operating characteristic curve. Results: In 1,253 HCV patients, overall SVR rate was 86.1% (95% CI = 84.1%, 88.0%). The AUCs of the four final candidate models were: ≥80% = 0.576; ≥50% = 0.605; ≥40% = 0.684; all = 0.681. The best performing model (≥40%) had significantly better predictive ability than the ≥50% (p = 0.03) and ≥80% models (p = 0.02). Strongest predictors of treatment failure were older age, history of hepatocellular carcinoma, and private (vs. government) insurance. Conclusion: This study highlighted baseline factors associated with HCV treatment failure. Treatment failure prediction may facilitate development of data-driven clinical tools to identify patients who would benefit from interventions to improve SVR rates.

© 2020 The Author(s). ; [INTRODUCTION]: Hepatitis C virus (HCV) infection has been related to increased cardiovascular (CV) risk. The aim of this study was to analyze the impact of sustained virological response (SVR) on endothelial dysfunction and subclinical atherosclerosis in patients with hepatitis C virus treated with direct-acting antiviral agents. [METHODS]: A total of 114 patients were prospectively recruited and underwent CV risk assessment including (i) endothelial dysfunction determined through laser Doppler flowmetry and (ii) subclinical atherosclerosis, elucidated by the ankle-brachial index (ABI). Atherogenic lipid profile (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides); markers of oxidative stress (oxidized low-density lipoprotein antibodies [OLAbs]), soluble markers of adhesion (vascular cell adhesion molecule [VCAM], e-selectin, and soluble markers of angiogenesis; and vascular endothelial growth factor, endothelial [EMPs] and platelet [PMPs] apoptotic microparticles, and cell-free DNA [cfDNA]) were measured. All determinations were performed at baseline, 12 weeks (SVR time), and 1 year after treatment. [RESULTS]: In patients with endothelial dysfunction, area of hyperemia improved after virus clearance (P = 0.013) and was related to significant decrease in VCAM, e-selectin (P < 0.001), and cfDNA (P = 0.017) and to increased OLAb levels (P = 0.001). In patients with subclinical atherosclerosis at baseline, a significantly improved ABI was seen after HCV clearance (P < 0.001). Levels of both EMPs and PMPs also decreased after SVR and at follow-up (P = 0.006 and P = 0.002, respectively). [DISCUSSION]: HCV clearance improved not only liver function but also endothelial dysfunction and subclinical atherosclerosis promoted by decrease in levels of VCAM, e-selectin, cfDNA, and PMPs and EMPs. ; Postdoctoral fellowship from the Spanish Government (Juan de la Cierva fellowship FJC1-2014-21675). Instituto de Salud Carlos III Project GLD17/00203.

The global plan to eradicate hepatitis C virus (HCV) led by the World Health Organization outlines the use of highly effective direct‐acting antiviral drugs (DAAs) to achieve elimination by 2030. Identifying individuals with active disease and investigation of the breadth of diversity of the virus in sub‐Saharan Africa (SSA) is essential as genotypes in this region (where very few clinical trials have been carried out) are distinct from those found in other parts of the world. We undertook a population‐based, nested case‐control study in Uganda and obtained additional samples from the Democratic Republic of Congo (DRC) to estimate the prevalence of HCV, assess strategies for disease detection using serological and molecular techniques, and characterize genetic diversity of the virus. Using next‐generation and Sanger sequencing, we aimed to identify strains circulating in East and Central Africa. A total of 7,751 Ugandan patients were initially screened for HCV, and 20 PCR‐positive samples were obtained for sequencing. Serological assays were found to vary significantly in specificity for HCV. HCV strains detected in Uganda included genotype (g) 4k, g4p, g4q, and g4s and a newly identified unassigned g7 HCV strain. Two additional unassigned g7 strains were identified in patients originating from DRC (one partial and one full open reading frame sequence). These g4 and g7 strains contain nonstructural (ns) protein 3 and 5A polymorphisms associated with resistance to DAAs in other genotypes. Clinical studies are therefore indicated to investigate treatment response in infected patients. Conclusion: Although HCV prevalence and genotypes have been well characterized in patients in well‐resourced countries, clinical trials are urgently required in SSA, where highly diverse g4 and g7 strains circulate.

The global plan to eradicate hepatitis C virus (HCV) led by the World Health Organization outlines the use of highly effective direct‐acting antiviral drugs (DAAs) to achieve elimination by 2030. Identifying individuals with active disease and investigation of the breadth of diversity of the virus in sub‐Saharan Africa (SSA) is essential as genotypes in this region (where very few clinical trials have been carried out) are distinct from those found in other parts of the world. We undertook a population‐based, nested case‐control study in Uganda and obtained additional samples from the Democratic Republic of Congo (DRC) to estimate the prevalence of HCV, assess strategies for disease detection using serological and molecular techniques, and characterize genetic diversity of the virus. Using next‐generation and Sanger sequencing, we aimed to identify strains circulating in East and Central Africa. A total of 7,751 Ugandan patients were initially screened for HCV, and 20 PCR‐positive samples were obtained for sequencing. Serological assays were found to vary significantly in specificity for HCV. HCV strains detected in Uganda included genotype (g) 4k, g4p, g4q, and g4s and a newly identified unassigned g7 HCV strain. Two additional unassigned g7 strains were identified in patients originating from DRC (one partial and one full open reading frame sequence). These g4 and g7 strains contain nonstructural (ns) protein 3 and 5A polymorphisms associated with resistance to DAAs in other genotypes. Clinical studies are therefore indicated to investigate treatment response in infected patients. Conclusion: Although HCV prevalence and genotypes have been well characterized in patients in well‐resourced countries, clinical trials are urgently required in SSA, where highly diverse g4 and g7 strains circulate.

The global plan to eradicate hepatitis C virus (HCV) led by the World Health Organization outlines the use of highly effective direct-acting antiviral drugs (DAAs) to achieve elimination by 2030. Identifying individuals with active disease and investigation of the breadth of diversity of the virus in sub-Saharan Africa (SSA) is essential as genotypes in this region (where very few clinical trials have been carried out) are distinct from those found in other parts of the world. We undertook a population-based, nested case-control study in Uganda and obtained additional samples from the Democratic Republic of Congo (DRC) to estimate the prevalence of HCV, assess strategies for disease detection using serological and molecular techniques, and characterize genetic diversity of the virus. Using next-generation and Sanger sequencing, we aimed to identify strains circulating in East and Central Africa. A total of 7,751 Ugandan patients were initially screened for HCV, and 20 PCR-positive samples were obtained for sequencing. Serological assays were found to vary significantly in specificity for HCV. HCV strains detected in Uganda included genotype (g) 4k, g4p, g4q, and g4s and a newly identified unassigned g7 HCV strain. Two additional unassigned g7 strains were identified in patients originating from DRC (one partial and one full open reading frame sequence). These g4 and g7 strains contain nonstructural (ns) protein 3 and 5A polymorphisms associated with resistance to DAAs in other genotypes. Clinical studies are therefore indicated to investigate treatment response in infected patients. Conclusion: Although HCV prevalence and genotypes have been well characterized in patients in well-resourced countries, clinical trials are urgently required in SSA, where highly diverse g4 and g7 strains circulate.

The global plan to eradicate hepatitis C virus (HCV) led by the World Health Organization outlines the use of highly effective direct‐acting antiviral drugs (DAAs) to achieve elimination by 2030. Identifying individuals with active disease and investigation of the breadth of diversity of the virus in sub‐Saharan Africa (SSA) is essential as genotypes in this region (where very few clinical trials have been carried out) are distinct from those found in other parts of the world. We undertook a population‐based, nested case‐control study in Uganda and obtained additional samples from the Democratic Republic of Congo (DRC) to estimate the prevalence of HCV, assess strategies for disease detection using serological and molecular techniques, and characterize genetic diversity of the virus. Using next‐generation and Sanger sequencing, we aimed to identify strains circulating in East and Central Africa. A total of 7,751 Ugandan patients were initially screened for HCV, and 20 PCR‐positive samples were obtained for sequencing. Serological assays were found to vary significantly in specificity for HCV. HCV strains detected in Uganda included genotype (g) 4k, g4p, g4q, and g4s and a newly identified unassigned g7 HCV strain. Two additional unassigned g7 strains were identified in patients originating from DRC (one partial and one full open reading frame sequence). These g4 and g7 strains contain nonstructural (ns) protein 3 and 5A polymorphisms associated with resistance to DAAs in other genotypes. Clinical studies are therefore indicated to investigate treatment response in infected patients. Conclusion: Although HCV prevalence and genotypes have been well characterized in patients in well‐resourced countries, clinical trials are urgently required in SSA, where highly diverse g4 and g7 strains circulate. ; Supported by the Medical Research Council (MRC) (MC_UU_12014/1) and Wellcome Trust (102789/Z/13/A) (to E.T.). M.S. is funded by the Wellcome Trust Sanger Institute (WT098051), the National Institute for Health Research Cambridge Biomedical Research Centre, the African Partnership for Chronic Disease Research (MRC UK partnership grant number MR/K013491/1), and the UK MRC (G0901213‐92157, G0801566). P.K. is funded by the UK MRC and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement. J.S. is funded by the MRC Confidence in Concept award to the University of Glasgow (MC PC 16045). G.M. is a Gates Cambridge Scholar supported by the Gates Cambridge Trust.